text
stringlengths 1
32.7k
| meta
dict |
|---|---|
The study is an NSABP sponsored multi-center randomized trial to determine if tamoxifen in a daily dose of 20 mg reduces the risk of developing breast cancer compared to placebo. Women eligible for the study include women over the age of 60 or women 35 to 59 who have an estimated risk of developing breast cancer similar to that of a 60 year old woman. Participants take study pills for 5 years. We stopped enrolling women to the study in 1993; NSABP closed the study to enrollment in 1997. Over 50 women have been screened and 5 have been randomized. The majority of women refuse participation because of either potential side effects of tamoxifen or the wish to continue estrogen replacement therapy. One woman is now off the study after developing uterine cancer. Another woman went off the study because of side effects of the study pills. A third woman completed 5 years of taking study pills in November of 1997, and the last two women still taking study pills will stop taking the pills in February and July of 1998. Sally Brown, R.N., and Sue Markus, R.N., of the office of Dr. E. George Elias, will continue to collect reports of examinations, medical follow-up and history from all five women, at least through 1999. NSABP expects that enough information will be available to determine the preventive effects of Tamoxifen in 1999 or 2000.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Deep brain stimulation of the subthalamic nucleus (STN DBS) can provide substantial motor benefit yet occasional mood and cognitive side effects in Parkinson disease (PD). Current literature hypothesizes that downstream network level effects are a critical mechanism of STN DBS?s influence on motor and non-motor behavior, however our ability to test this hypothesis has been limited. Common imaging modalities either do not have the temporal resolution necessary to discern resting state functional connectivity of cortical networks or are not suitable or safe for patients with implanted DBS. We have developed a novel high-density diffuse optical tomography (HD-DOT) system for measuring brain hemodynamics which can accurately map the functional connectivity of cortical resting state networks (RSN) or task-evoked responses within the first ~1cm of cortex. HD-DOT has comparable temporal and spatial resolution to fMRI, greater comfort than MRI or PET, no radiation exposure, no electrical artifacts, no metal artifacts and no contraindications or safety concerns for DBS patients. We have strong preliminary data showing the validity and feasibility of assessing cortical RSNs and task-induced responses in STN DBS patients. With our novel HD-DOT system, careful experimental design and rigorous analyses, this study will determine the nature of cortical RSN-level modulation induced by STN DBS and its relationship to DBS-induced motor and cognitive change. Controls and individuals with PD will be enrolled pre-surgically and scanned with HD-DOT and MRI (resting state BOLD, structural]). After implantation and optimization of DBS, PD individuals will be scanned with HD-DOT in several conditions. With these data, we will test hypotheses about networks that are responsive to important characteristics of STN DBS (e.g.location) and their relationship to motor and non-motor function. This information ultimately could provide methods for faster optimization of DBS parameters and help identify cortical nodes or networks involved in STN DBS-induced benefits or side effects that would provide future targets for less invasive neuromodulation. Finally, this work could reveal fundamental properties of cortical network physiology such as the capacity for plasticity in response to up-stream perturbations.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The NARCH initiative will support partnerships of American Indian and Alaska Native (AI/AN) Tribes, Tribal organizations, or non-profit national or area Indian Health Boards, with institutions that conduct intensive academic-level biomedical and behavioral research;these partnerships are called Native American Research Centers for Health.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The goal of the proposed research is to elucidate the molecular mechanisms whereby an excitable cell exerts a trophic influence on another excitable cell. The work will be carried out in tissue culture using cloned lines of nerve and muscle cells. Trophic effects will be monitored using a variety of probes. Purified neurotoxin and anti-acetylcholine receptor antibody will be used to investigate the mechanisms whereby a nerve cell regulates the synthesis, and distribution on the limiting cell membrane, of acetylcholine receptors in the nerve or muscle being innervated. Various animal and microbial toxins, specific antisera, and several enzyme activities will be used to detect and investigate trophic interactions between nerve and muscle and between nerve and nerve. The interaction of excitable cells in tissue culture will be investigated with emphasis on cell specificity and molecular mechanisms involved. The investigation of molecular mechanisms will center on the role of membrane-membrane interaction, and the role of putative trophic factors thought to act on the target cell.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The Patient-Centered Medical Home and the Chronic Care Model have emerged as complementary frameworks to achieve the Institute of Medicine's goals for high-quality preventive and chronic disease care and to help contain healthcare costs. These models emphasize patient-centered care, including self-management support (SMS), population management, coordinated care teams, improved information systems, and active quality improvement. The effective application of these models in primary care for patients with type 2 diabetes (T2DM) remains a challenge, especially in the key area of SMS. SMS programs are important because they prevent, delay, or reduce over time the complications of T2DM and cardiovascular diseases. Few tools are available to help primary-care clinicians identify, monitor, and intervene on unhealthful lifestyle behaviors and problematic psychosocial factors over time for patients with T2DM. Interactive behavior-change technology can facilitate the adoption of crucial SMS interventions in primary care for patients with T2DM and related health risk behaviors. To be effective, the technology must be well-integrated into the practice system, be cost- and time-efficient, and enhance and complement - but not replace - interactions between patients and primary-care teams. To meet the need for effective SMS intervention, we have developed and tested Connection to Health (CTH), a comprehensive, evidence-based SMS program that uses targeted conversations between primary-care clinicians and patients with T2DM to help improve clinically important diabetes-related health outcomes and resolve self-management problems. Uptake and maintenance of programs such as CTH in primary care have been limited by the inability of practices to adapt and implement program components into their culture, patient flow, and work processes. Practice coaching has been shown to be effective in helping practices make the changes required for optimal program implementation. The proposed research is designed to promote the translation of SMS into primary-care practices for patients with T2DM by combining two promising lines of research, specifically, (a) testing the effectiveness of CTH for patients with T2DM in diverse primary-care practices, and (b) evaluating the impact of practice coaching to enhance uptake and maintenance of the intervention.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The aim of this project is to use epidemiologic methods in a randomized clinical trial to test the effects of a psychosocial intervention to improve functional ability in elderly stroke patients. The proposed intervention is designed to mobilize the social networks of stroke patients, comprised for the most part of family and close friends, to provide effective emotional and instrumental support and increase the patient's sense of self-efficacy regarding ability to regain function. This intervention is tailored specifically to the needs of individual stroke patients, their families and support systems and is designed to occur in 15 meetings over a 6 month period. Stroke patients (n=290) from the 2 major hospitals in New Haven will be randomly allocated to the psychosocial intervention (PSI) and usual care (UC) groups. Primary endpoints are assessed at 3 and 6 months and are based on self-reports and performance-based assessments of functional ability. Several longitudinal epidemiological studies have reported that social support influences recovery of functional ability both in terms of physical functioning and psychological adjustment in stroke patients. Furthermore a number of observational cohort studies have indicated that lack of social support is related to increased mortality, especially case- fatality. Finally, several recent intervention studies have shown that psychosocial interventions have led to improved psychosocial adjustment in stroke patients and longer survival in patients with other chronic illness. Important components of these interventions have been focused on improving or providing support to patients with chronic illness and improving family functioning. To date, no interventions have focused specifically on the outcome we consider to be a critical one - improvement in physical functioning. Our aim is to employ rigorous clinical trial methodology to test the effectiveness of a psychosocial intervention to improve functioning in elderly stroke patients.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Despite the peripheral nervous system's (PNS) intrinsic capability to regenerate following injury, permanent dysfunction of the PNS is common. Researchers have developed biodegradable conduits from diverse materials in an effort to find a new way to address the degeneration of PNS myelin and axons, and to bypass risks associated with current treatments for injury. Several conduits have entered clinical use, but regeneration with these devices is highly variable and none has been able to stimulate repair across large nerve gaps that exceed 3 cm in humans. There is a critical need for therapies that enhance peripheral nerve regeneration (PNR) after injury or the dysfunction that results from prolonged disease states, such as diabetes or polyneuropathies. It is widely accepted that in order for a conduit-based therapy to stimulate regeneration of large nerve gaps and to reproducibly stimulate regeneration of smaller nerve gaps, a biological enhancer is needed. Many enhancers, such as recombinant proteins, cells and cellular components, have proven effective in small animal models and have even been translated into larger animal models, but none has entered the clinic. A key reason is the lengthy and costly regulatory process needed to evaluate complex biologicals for human use. One compound tested in animal models with biodegradable conduits is polysialic acid (PSA), which promotes cell migration and axonal elongation. Following PN injury, PSA is greatly upregulated in motoneurons and Schwann cells. Exogenously supplied PSA has promoted regeneration after acute damage to the femoral nerve and spinal cord of adult mice. We have identified a small molecule, tegaserod, with the potential to act as a mimetic for PSA. This proposal focuses on testing a novel small molecule polysialic acid mimetic as a potential therapeutic for peripheral nerve injury. has been approved by the FDA for a different indication, acting via an entirely different mechanism of action. This project proposes to retask tegaserod for PNR. Our preliminary data indicates that tegaserod stimulates neuronal behavior in a manner and pathway consistent with PSA. Importantly, this stimulation appears to be independent of tegaserod's established mechanism of activity as a 5-HT receptor agonist. Supplementing our in vitro data is an in vivo study that showed mice receiving tegaserod within a conduit improved following femoral nerve injury significantly more than mice that received the vehicle control. Tegaserod, as a small molecule, does not carry the biological risks of transplanted cells and xenogeneic proteins and is likely to face a considerably smoother pathway for clinical entry. This proposal outlines the experiments necessary to determine the potential of tegaserod for PNR and clinical translation. In vitro experiments and in silico molecular modeling will further assess the mechanism by which tegaserod stimulates neural regeneration. Simultaneously, we will conduct experiments that determine the optimal treatment dose of tegaserod delivered to nerves in a more stringent animal model, as well as develop methods for a more sustained delivery that we hypothesize will be necessary for even larger gap sizes. Achieving these experimental goals will set the stage for future pre-clinical animal models, and clinical trials. PUBLIC HEALTH RELEVANCE: To address a need for improved devices for peripheral nerve regeneration after nerve injury, we have identified a compound, tegaserod, previously approved by the FDA that we have found to mimic the pro-repair molecule polysialic acid. Tegaserod will be tested in critical size defects in an animal model, both encapsulated in a hydrogel as well as gradually released from polymeric nerve conduits, to optimally regenerate peripheral nerve. !
|
{
"pile_set_name": "NIH ExPorter"
}
|
ABSTRACT Diabetes mellitus results when pancreatic beta cells fail to produce enough insulin to maintain glucose homeostasis, either due to beta cell destruction (T1D) or insulin resistance (T2D). Beta cell failure can result from loss of beta cell number, reduced insulin secretory function, or both. Two important goals in diabetes research are to understand the causes of islet failure and to find therapies that restore functional beta cells. To date, my group has focused on identifying ways to increase beta cell mass by inducing proliferation of endogenous beta cells. We recently made the surprising, but in retrospect logical, observation that engaging mild ER stress stimulates beta cell proliferation (Sharma et al, JCI 2015). This concept suggests a beta-cell-autonomous explanation for compensatory beta cell proliferation in response to increased insulin demand. We have traced the proliferative signal to Atf6, which is one of three canonical UPR signaling pathways. Stepping back, Atf6 is a transcription factor which may play an important role in pancreatic islet function but whose biology is, to date, relatively unexplored in this tissue. Loss of Atf6 has been linked to human diabetes risk, and experiments in mice suggest that beta cell Atf6 activity protects against diabetogenic insults. Current understanding of Atf6 biology suggests several possible mechanisms by which Atf6 may be beneficial for beta cell health, including not only proliferation but also insulin production and secretion, maintenance of beta cell differentiation status, and promoting beta cell survival. Experiments in this project will explore Atf6 roles in healthy beta cell adaptation to insulin demand, assessing both proliferation and function. We will define mechanisms downstream of Atf6, using both candidate and unbiased approaches to identify Atf6 transcription targets in mouse and human islets. Finally, we will determine how Atf6 loss undermines beta cell capacity to stand up to diabetogenic stimuli. To accomplish these studies we have assembled a strong team of beta cell ER stress experts (Peter Arvan, Raghu Mirmira, Fumi Urano) and an Atf6 expert (Luke Wiseman). With technical support from the UMass MMPC (Jason Kim), the Indiana Diabetes Research Center (Raghu Mirmira), and the UMass Deep Sequencing and Bioinformatics cores (Maria Zapp, Alper Kucukural, Nick Merowsky) we have all the tools in hand to move this important work forward.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The smooth muscle layers of the gastric fundus generate tonic contraction or relaxation and are critical in the regulation of gastric volume. Upon food ingestion the proximal stomach relaxes to accommodate the increases in gastric volume without concurrent changes in gastric pressure. This accommodation, known as adaptive relaxation, is under both intrinsic and extrinsic neural control. Vagal afferent stretch sensitive fibers located in the muscle layers are stimulated by gastric distension and trigger vagovagal efferent and local enteric pathways that increase gastric motility and gastric emptying. Millions of patients with functional dyspepsia and gastroparesis, both idiopathic and that associated with diabetes mellitus, have low vagal tone and impaired postprandial gastric meal accommodation which is often accompanied with symptoms of abdominal pain, bloating and nausea. Using a combined morphological and physiological approach, the broad long term objective of the present study is to determine the changes which occur in vagal and enteric afferent sensitive mechanisms that are associated with dramatic changes in gastric accommodation in animals lacking interstitial cells of Cajal (ICC). To address this main objective, the specific aims of this project will examine the importance of interstitial cells of Cajal (ICC), which are found as intramuscular arrays in the muscle layers of the stomach in: I) The development, guidance and maintenance of vagal afferent fibers in the stomach. ii) Whether ICC possess in-series stretch sensitive channels that could trigger afferent pathways and stomach accommodation. iii) To determine the role of ICC in gastric accommodation and whether loss of ICC affects vagal afferent discharge and gastric accommodation in mutant mice lacking ICC. These studies work will be combined with structural studies to determine the morphological relationships between vagal afferent arrays and intramuscular ICC in adult and developing animals. Experiments outlined in this proposal will provide important novel information on the role of ICC in afferent stretch sensitivity in the stomach. This information could also be extended to other organs of the gastrointestinal tract. In doing so we will aid future studies toward understanding how these cells may be critical in pathophysiological disease states.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Blood cell production in the acute settings of trauma, surgery, sepsis, sickle cell crisis and after stem cell transplant is critical for survival and yet is often dysfunctional in those settings. We have recently used a single cell, proximity based analysis to define a distinctive mesenchymal cell subpopulation in the bone marrow that differentially expresses molecules governing hematopoietic stem and progenitor quiescence. These molecules, IL-18 and angiogenin are differentially regulated with stress and we hypothesize, participate in dysfunctional hematopoiesis. We seek to define the role of these specific molecules in models of sepsis and transplant to determine if modulating them will improve blood cell production and survival. Further, we seek to extend the advantage of defining specific subsets of marrow stromal cells more broadly and propose unbiased, single cell analytic tools to define the complexity of marrow stroma and how it may be altered in settings of stress.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The intravenous injection of F1 hybrid mice with parental T cells result in a loss in the ability of the F1 mice to generate T-cell mediated immune responses in vitro to graft-versus-host immune deficiency (GVHID). Recognition of host class II MHC antigens by donor cells is required to initiate GVHID. Recognition of host class I MHC antigens doesn't induce GVHID. Recognition of class II only results in loss of self + X responses but not of allogeneic responses; recognition of class I and II results in loss of self + X and allogeneic responses. Induction of GVHID by class I and II recognition requires both L3T4+ and Lyt2+ cells; induction of GVHID by class II only recognition requires only L3T4+ parental T cells. GVHID is accompanied by loss of ability to produce IL 2 and in loss of expression of IL 2 receptors. This IL 2 loss was observed in both class I and II and class II only GVHID. Recovery of immune function from GVHID was preceded by recovery of IL 2 receptor expression and IL 2 production. GVHID was used to abrogate natural resistance to bone marrow grafts in F1 hybrid mice.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Overall Program The overall goal of this NCDDG is to develop our lymphoid cancer targeting peptidomimetic leads into useful therapeutic and imaging agents. Through combinatorial chemistry, we have identified a series of peptidomimetic compounds that bind to activated oc4|31 of lymphoid malignancies. These compounds contain an organic moiety, D-amino acids, and unnatural amino acids, and therefore they are expected to be resistant to proteolysis. They bind to both T- and B-lymphoma cell lines as well as fresh leukemia cells derived from patients with acute lymphocytic leukemia, but they do not bind to normal human peripheral blood. Furthermore, they bind strongly to dog lymphoma cells. These peptidomimetic leads have great potential to be developed into therapeutic and imaging agents for both human and canine lymphoid malignancies. This NCDDG application has three programs and two cores. Program 1 is responsible for further optimization and characterization of these peptidomimetic leads. Computational chemistry and combinatorial chemistry will be used for lead optimization. Program 2 involves the use of a series of CHO cells, that have been stably transfected with wild type or mutant a4 and/or pi integrin genes, to evaluate the molecular interactions between a4pl integrin and the targeting agents developed in Program 1. This study will enable us to map the binding site, and to develop high affinity ligand analogues that can overcome the mutation of the critical residues on the integrin. Program 3 involves in vivo evaluation of the targeting agents, developed in Program 1 and synthesized by Core B. DOTA-labeled targeting agents will be loaded with ^Cu for PET imaging and 90Y for therapeutics studies in nude mice with human lymphoma xenograft, and in spontaneous canine lymphoma in companion dog. Core A is the administrative core. The synthetic chemistry core (Core B), with input from corresponding programs, will be responsible for the design and synthesis of compound-bead libaries, targeting agents, and any other chemical conjugates required by all three programs. Program 1, 2, and 3 as well as Core B are highly interactive and synergistic. Our goal is to fully optimize and evaluate the targeting potential of our radio-targeting agents for lymphoid malignancies by the end of year 5, at which time one targeting agent will be selected for clinical development.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Chronic superficial wounds are difficult to treat and often never completely heal. Diabetic foot complications account for the majority of lower limb amputations in the world, and 25% of all diabetic hospital admissions in the US. The standard of care for these wounds has been unchanged for decades, and remains reduced weight bearing, debridement, antibiotics, and dressings. Other therapies have been examined, including vacuum-assisted closure devices, biomaterial-based dressings, and growth factor therapies. Their impact has been marginal, with little clinical improvement over placebo controls, and often with increased risk of complications. Growth factor therapy, while promising, has not translated into dramatic clinical success with high doses of single exogenous factors. For example, Regranex topical gel (high dose recombinant platelet- derived growth factor), improves closure of diabetic ulcers but with an increased retrospective incidence of cancer. CytoSolv, Inc., has developed technology to simultaneously deliver multiple regenerative factors derived from cultured choroid plexus (CP) to accelerate wound healing at low therapeutic doses. These factors are present in the cerebrospinal fluid of normal adults, as the CP forms the blood- cerebrospinal fluid barrier and is involved in growth factor maintenance. Vascular endothelial growth factor, platelet derived growth factor, connective tissue growth factor, and transforming growth factor beta are among hundreds of potentially regenerative factors secreted by the CP. The synergy of the collective activities of CP factors allows CytoSolv's technology to potentially overcome the limitations and side effects of mono-factor therapy by delivering lower doses over reduced treatment duration. Pilot studies using lyophilized CP factors to treat wounds in normal rats revealed faster healing and vastly improved histological quality of healed tissue compared to topical antibiotic controls, including features such as hair follicles and other dermal appendages. These findings, coupled with the impressive portfolio of bioactive agents in the CP secretome, provide support for continued investigation. The potential clinical applications of an acellular CP product are numerous, but diabetic ulcers represent the greatest unmet need and our first target. The extent of ischemic disease in these individuals could be well served by the multiple biologic activities contained within the CP transcriptome. The proposal contained within this SBIR application seeks to (i) continue development of a topical product by incorporating factors secreted by the CP in culture supernatant into a non-occlusive dressing that provides at least 24 hours of continuous factor delivery, as determined in vitro;and (ii) assess the formulated product in open wounds created in the splinted db/db mouse model of Type I diabetes. These projects will provide fundamental data within a 6-month time frame that will allow the company to continue its goal developing a topical product to rebuild damage tissue in diabetic ulcers, and may also uncover additional information relevant to the pursuit of alternative disease indications. PUBLIC HEALTH RELEVANCE: The naturally occurring cocktail of bioactive molecules secreted by the choroid plexus is being developed by CytoSolv, Inc., as a topical regenerative product for accelerating superficial wound healing. The factors, which include many that are currently used in high dose mono-therapies to treat various forms of problematic wounds, range in biological activity from inflammation, to angiogenesis, to tissue rebuilding, and have demonstrated the ability to accelerate and improve the quality of wound repair in pilot studies in normal animals. CytoSolv aims to further characterize, formulate, and assess this early stage product in db/db diabetic mice, representing a stringent wound model with inherent healing impairments that mimic the company's target indication, diabetic ulcers.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objective of the Core Grant for Vision Research are: (1) to increase knowledge concerning normal vision; (2) to apply this knowledge to the preservation and restoration of human vision. To achieve these overall scientific goals, a multidisciplinary research program has been developed. Related to the eye and vision, this program consists of the following major basic science and clinical research components: Molecular Biology, Biophysics, Electrophysiology, Microbiology and Immunology, Ophthalmic Pathology, Ophthalmology-Retina and Lens Disease Research, Pediatric Ophthalmology Research, AIDS-related Eye Disease Research, and Vision-related Genetic Disorders. Appropriately interrelated, the major components of this program apply wide spectrum of laboratory and clinical methods of investigation to an extensive array of research projects. The Jules Stein Eye Institute Vision Research Center consist of 13 Principal Investigators with 12 active R01 grants, 2 R01 grants pending, as well as 2U10 grants. Support is requested for the following Core Modules: 9001 Biochemistry; 9002 Molecular Biology; 9003 Electron Microscopy. Photography; and 9004 Machine Shop. These Core facilities provide the backbone support for each individual investigator and are essential to the success of each project. The Core facilities and Core support are instrumental in fostering collaboration among the Institute members and with scientists in other institutions worldwide.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Summary(Overall) The overarching goal of this Program Project is to better understand the Developmental Mechanisms of Trachea-Esophageal Birth Defects (TEDs) in order to advance our knowledge of their etiology, enhance diagnosis, improve treatment, and inform strategies to generate TE tissue from human pluripotent stem cells (PSCs) that might ultimately be used for transplantation The trachea and esophagus (TE) arise from the separation of a common foregut tube during early fetal development. Defects in TE morphogenesis cause a spectrum of life-threatening TEDs that prevent proper breathing and feeding in newborns. TEDs including esophagealatresia(EA)andtrachea-esophagealfistula(TEF)arecorrectedbyinvasiveneonatalsurgeryand areoftenassociatedwithlong-termco-morbidity.TheetiologyofTEDs,whichoccurin~1:3500births,ispoorly understood. Although there is compelling evidence for a major genetic component, causative mutation are. only known in ~12% of TED cases worldwide. Moreover, even for the few cases where the genes involved havebeenidentified,suchastheHEDGEHOG(HH)andBMPsignalingpathwaygenes,howtheseregulate fetalTEmorphogenesis,andhencethestructuralbasisofTEDs,isunknown.Thelong-termgoalofthisproject is to determine the genetic and developmental mechanisms underlying TEDs in order to improve our understanding of their etiology, enhance diagnosis, improve treatment, and inform strategies to generate human tissue from pluripotent stem cells (PSCs) that might ultimately be used for transplantation. We have assembled an experienced and highly collaborative multi-disciplinary team of clinicians, geneticists, bioinformaticians,datascientists,imagingexperts,developmentalbiologistsandhumanstemcellbiologiststo tackle this problem using an innovative combination of human genetics, neonatal MRI, animal modeling in Xenopus and mouse, quantitative cell biology, genome editing and human PSCs derived esophageal organoids.ThiswillbeaMulti-PIprojectcenteredatCincinnatiChildren?sHospitalMedicalCenter(CCHMC)in collaboration with Columbia University Medical Center. The Multi-PIs will be: Aaron Zorn PhD (contact PI;? CCHMC), Paul Kingma MD PhD (CCHMC), James Wells PhD (CCHMC) and Wendy Chung MD PhD (Columbia). These combined expertise and resources creates a synergistic program not found at any single institution.Wepropose3innovativeandhighlysynergisticprojectsandaGenomicsCoretorevealthegenetic, molecularandcellularbasisofTED Project-1:ComprehensivephenotypicandgeneticassessmentofTEDpatients. Project-2:ModelingthemolecularandcellularmechanismsofTEDsinanimals. Project-3:ModelingTEbirthdefectsinhumanpluripotentstemcell(PSC)-derivedfetaltissues. IntegratedGenomicsCoreandAdministrativeCore
|
{
"pile_set_name": "NIH ExPorter"
}
|
This work proposes to develop and test the performance of a low-cost, easy to use, disposable sampler to measure personal exposures to inhalable aerosols in the workplace. To improve the likelihood of future adoption by exposure assessors, the sampler will incorporate a redesign of the inlet cap of the 37-mm sampling cassette, the most commonly used particle sampler in the U.S. The sampler inlet will be designed to sample large particles with efficiency to match the international performance criterion for inhalable aerosol sampling. As such, the sampler will capture particles with the same efficiency as a worker's mouth and nose. This research will: (a) use computational fluid dynamics modeling tools to investigate how inlet geometries affect sampling efficiency, to optimize the sampler inlet, and to estimate an orientation-averaged sampling efficiency for the prototype sampler(s) to compare to the inhalable criterion; (b) investigate the sampling efficiency of the prototype sampler in a low-velocity wind tunnel and a calm-air chamber to quantify accuracy, precision, linearity, and internal losses, in controlled environments; and (c) field test and validate the sampler performance in three manufacturing settings and compare the sampling efficiencies to existing devices. Within the third aim, one of the worksites will examine both exposure and indicators of respiratory inflammation in the workers to examine whether exposures measured with the new inhalable sampler improve the measurements of association of health outcomes. This project addresses multiple NORA sectors (construction, manufacturing, refining, mining, and agriculture) as well as NORA Exposure Assessment cross-sector goals, including developing/improving methods to assess worker exposures to critical occupational agents and validation of these methods to provide and characterize their performance. The long-term outcome of this project includes the advancement of tools to improve exposure assessment evaluations. By increasing the adoption of physiologically-relevant exposure assessment tools, data-driven risk-based exposure limits for hazardous aerosols can be improved to protect worker health. PUBLIC HEALTH RELEVANCE: This project will develop a low-cost, easy to use, disposable particle sampler that estimates how much dust is inhaled by a worker. This sampler will advance our understanding of biologically-relevant exposures and improve our ability to understand the risk of disease that results from occupational dust exposures. This information will empower decisions that can reduce exposures and prevent occupationally-related illness.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Rotaviruses (RV) are the single most important cause of severe diarrhea in infants and young children worldwide. These viruses are also common causes of disease in healthy adults, the elderly and the immunocompromised. Virtually all mammalian species are efficiently infected with their own homologous host- species RV but not by heterologous RV. Recently, effective, live attenuated RV vaccines became commercially available, but their mechanisms of action and molecular basis for attenuation are not understood. Infection with RV is predominantly restricted to the villous epithelium of the small intestine. Of note, the basis for host-range restriction of heterologous RV replication in intestinal cells remains unknown. Due to their relatively small genomic size, host-range and tissue tropism, rotaviruses are a highly tractable model system for study of the interaction between host epithelium and enteric pathogens. RVs are also potential vectors for targeting the human small bowel epithelium and an ideal system for assessing vaccination strategies against enteric pathogens. It is our objective to continue studies of RV-host interactions with the goal of better understanding enteric microbial pathogenesis. The specific aims of the proposal are to: 1) Characterize the genetic basis for host-restricted intestinal cell tropism of selected homologous and heterologous RVs using viral reassortants in a murine model. It is our hypothesis that one of the RV surface proteins (VP4), which mediates cell entry and the RV IRF3 antagonist protein, NSP1, which blocks the host interferon response, are responsible for determining the phenotype of host restricted intestinal replication. 2) Characterize early events in RV cell entry in an in vitro model of polarized epithelium and determine the conformations of VP4 and VP7 that mediate cell entry. It is not clear how the large, non-enveloped icosahedral RV particle enters the cytoplasm of a polarized enterocyte. We will use a combination of highly specific monoclonal antibodies, confocal microscopy and cell biologic techniques to illuminate this process. Cell entry events contribute to the varying intestinal cell tropisms of different homologous and heterologous RV strains. We hypothesize that the entry process is characterized by critical changes in the structure and cellular localization of the two RV surface proteins. 3) Develop a tractable reverse-genetics system to manipulate the genome of a replication competent rotavirus. In order to take RV pathogenesis and cell entry studies to the next level, methodologies to directly modify the RV double-stranded, segmented RNA genome are needed. Such a system will also potentially enable us and other investigators to utilize the exquisite entero-tropism of RVs to design unique targeting vectors for other infectious diseases. It is our hypothesis that we can accomplish this aim by utilizing approaches recently validated for reovirus and orbiviruses. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Acute enteric infections in general and rotavirus infections in particular are a cause of considerable morbidity both in children and in adults, especially the elderly and immunocompromised. They are also important causes of morbidly for members of our armed services and our veteran population. In addition, understanding the nature of the interaction between pathogens that infect the gastrointestinal tract and the host has substantial relevance to our efforts to promote better biodefense strategies. The studies proposed here will yield better understanding and increased knowledge of the microbial pathogeneses that cause enteric diseases in man.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The goal of this project is to determine the mechanism(s) by which microencapsulation of donor islets and CTLA4-Ig treatment of recipient synergize to permit long-term survival of neonatal porcine islet xenografts in spontaneously diabetic NOD mice. There is a critical need for better insulin therapy to circumvent complications of insulin-dependent diabetes mellitus (IDDM). Our long-term goal is to develop techniques for transplantation of microencapsulated, xenogeneic islets to provide a durable, physiological source of insulin to diabetic patients. Microcapsules are the most promising technique for protecting donor islets from host immune destruction. Our capsules are biocompatible and xenogeneic pig islets in these capsules function>100 days in mice with chemically induced (SZN) diabetes, showing that factors required for long-term function of xenogeneic islets are available. Capsules protect xenografts by preventing host sensitization. NOD mice (with spontaneous diabetes) destroy encapsulated neonatal pig islets in 3 weeks. Biopsies reveal activated macrophages, immunoglobulins, IL-1, TNF, IFN-g, and IL-10. We postulate that NOD rejection is initiated by donor antigens that are shed from encapsulated islets and processed via the MHC class II pathway by host APC. These APC activate NOD CD4+ T-cells that mount a Th1 response, with donor islet destruction via cytokines. Survival of encapsulated pig islets in NODs is significantly prolonged (>100 days) by blocking NOD T-cell activation with CTLA4-Ig. We will test the hypothesis that CTLA4-Ig combined with microencapsulation alters the repertoire of NOD T-cells that recognize the cross-reactive antigens on neonatal pig islets. We will characterize in vitro NOD T-cell proliferative responses to porcine islets, using T-cell clones analyzed by flow cytometry, lymphokine ELISA and adoptive transfer in vivo to NOD-Scid mice. We will test the hypothesis that CTLA4-Ig plus microencapsulation induces donor-specific unresponsiveness (tolerance) by challenging with donor-specific, cryopreserved islets, skin, thyroid, and spleen cells. We will elucidate the cellular mechanism(s) responsible for CTLA4-Ig effects in this mode by substituting a mutant CTLA4-Ig which binds B7-1 selectively, or one which does not fix complement. We will test the hypothesis that preventing T-cell activation using a combination of reagents directed toward different immune response pathways will provide more robust protection against rejection, by treating NODs with anti-CD4 and anti-CD40L mAbs in conjunction with CTLA4-Ig.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The capability to design molecular function, i.e. to tailor molecular structure to impart a prescribed function, offers great potential for the development of science and technology. It is important to realize that the design of molecular function is the first step toward molecular engineering. Biomolecules, the paradigm of molecular design, exhibit marked diversity and unique functions. Fortunately, many of the biomolecules are rich in sensitive spectroscopic markers, lending themselves to careful scrutiny by a host of complimentary techniques. This resource proposed to extend and tailor current spectroscopic facilities to directly interrogate the structure <-> function <-> energy relationship of molecular design, analyze and assimilate these results with other existing knowledge about molecular function, and disseminate this information to the scientific and biomedical engineering community. Our existing time-resolved spectroscopy facilities [optical absorption, fluorescence, resonance Raman, pulsed laser photothermal, ESR, and x-ray absorption spectroscopies] will be extended to include simultaneous investigations of molecular function in real time, continuous data acquisition in time over many decades after initiation, with ~10-9 sec resolution. The resource facilities will include instrumentation for biochemical poise. Appreciation of the global significance of the investigations requires that the large amounts of data be analyzed rapidly and efficiently, ensuring that the maximum amount of information is extracted, visualized, and assimilated in terms of existing knowledge. The resource proposes tailoring existing computational facilities for mass data storage and manipulation using cost effective parallel processing hardware, a local area network, and specialized software tools. Interpretation and theoretical prediction of spectral features will provide additional tools for assimilation and aid in establishing molecular design parameters. Using these facilities, the resource proposes to focus its research activities to explore the design of molecular function of iron heme containing enzymes and proteins. These are exemplary of biomolecules and their potential high utility renders them of major importance to industry as well as to medicine and the environment. The resource proposes to develop a molecular design data base which encompasses spectroscopic and kinetic data obtained with resource facilities. In order to facilitate communication and dissemination, this information bank [together with the visualization and analysis tools] will be available to the scientific and biomedical engineering community via national computer networks. Further, the resource facilities for investigation of the design of molecular function will be accessible in a hands-on or remote mode. No such capability exists anywhere in the world.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Tardive dyskinesia remains a major public health problem in psychiatry. No proven safe and effective treatment has emerged for this condition and at present all marketed antipsychotic drugs appear capable of producing this adverse effect. Therefore, identification of risk factors and the development of strategies for prevention remain major goals. Knowledge regarding factors which might increase the risk for TD is largely based on cross- sectional prevalence surveys and retrospective data collection on important diagnostic, illness and treatment history characteristics. The continuation of the present prospective study would provide a unique opportunity to further develop our prospectively collected database on the incidence and course of tardive dyskinesia as well as factors influencing both of these. To date 955 patients have entered the study including 70 schizophrenic or schizophreniform patients with no prior exposure to neuroleptics at study entry and 135 patients receiving different controlled dosage ranges of fluphenazine decanoate. The median length of total previous neuroleptic exposure at study entry (for those who have been treated) is 12 months, therefore, patients who are being followed from the early part of their treatment course. Sixty-three patients with a documented history of severe parkinsonian side effects to neuroleptic medications are also being followed. The design of the study calls for patients to be evaluated every 3 months with the Simpson Dyskinesia Scale, the Simpson-Angus Scale and the BPRS. Patients with questionable signs of TD are seen monthly. Those developing presumptive TD are evaluated neuromedically, videotaped and seen every 2 weeks, with discontinuation of neuroleptic medication whenever possible. To date 160 cases of presumptive TD have developed and a major focus of the project at present is to investigate TD outcome and to evaluate the effect of prospectively assessed variables (both prior to and subsequent to the development of tardive dyskinesia) on its long-term course.
|
{
"pile_set_name": "NIH ExPorter"
}
|
PROJECT 2 SUMMARY/ABSTRACT Checkpoint blockade has thus far demonstrated clinical benefit in only a small fraction of pediatric cancers and emerging paradigms hold that this is largely due to their low mutational burdens. In contrast, CAR T cells directed toward B cell restricted antigens have demonstrated astonishing potency against B-ALL, despite low mutational burden. The recent FDA approval of tisagenlecleucel (Kymriah) for pediatric and young adult B-ALL is a watershed moment, representing the first cell based therapy approved for the treatment of cancer and the first gene therapy approved in the United States. Clinical and preclinical data with non-CD19 CAR T cells is providing increasing evidence that CAR therapeutics will demonstrate activity in AML, solid tumors and brain tumors in the coming years, driven largely by technological innovations in CAR engineering that will create safer and more potent therapeutics. This Project leverages advances in technology to improve fundamental understanding of the major factors currently limiting CAR efficacy and to develop next generation CAR T cells, designed specifically to overcome these challenges. Work on each aim will launch simultaneously and be conducted in parallel, however information gleaned in separate aims will directly inform the others during the course of the Project and enhance Project deliverables. Crosstalk with other Projects in the Center will be continual and extensive as described below. A major goal of our Center is provision of a comprehensive catalog of cell surface molecules expressed on high risk pediatric tumors in Project 1, and identification of ?antigen groups? that traffic together, driven by commonalities in genotype, microenvironment and/or cell lineage. In Aim 1, we will utilize MIBI and CyTOF to undertake ultra-high dimensional analysis of high risk pediatric cancers, and datasets generated will be interrogated by experts in computational science with Project 1 using algorithms equipped to identify patterns of antigen expression within histologically or genotypically associated groups, and inform approaches to develop multi-specific CAR T cells in Aim 2. Here, we leverage advances in in silico modeling and super resolution subcellular imaging to optimize engineering of these complex receptors, and we also test whether targeted gene integration, using CRISPR-Cas9 will render more potent multi-specific T cells than the traditional approach using retroviral/lentiviral vectors. Aim 3 takes a deep dive into the pathobiology of T cell exhaustion in CAR expressing T cells, and leverages innovative technologies for discovery (ATAC-Seq) and engineering (drug regulatable proteins) to create the first clinically applicable class of regulatable (e.g. remote controlled) CAR T cells. There will be substantial crosstalk between Aim 2 and Aim 3, as engineering advances used to overcome exhaustion can be readily applied to multi-specific CARs to further enhance potency. Further, this Project will interface substantially with Project 3, since delineation of major elements comprising the TME delivered by MIBI analysis of pediatric tumors, will inform selection of immunomodulators for study in the Project 3?s fully murine tumor models.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Any research center dedicated to stimulating, facilitating, and advancing a scientific program must be armed with the best tools to create, collect, weigh, and interpret evidence. In this regard, epidemiological, clinical and basic science studies in environmental health science usually require guidance in study design, data management and statistical analysis. The Biostatistics, Epidemiology, and Data Management (BEDM) Core will provide an interrelated network of talented specialists to be used as a resource by the community of NIEHS Center researchers. BEDM Core members will provide consultative, programming, and analytical expertise in study design, execution, data management and statistical analysis to NIEHS Center investigators and to pilot study investigators who are planning or conducting research through the Center. The specific aims of the BEDM core are: 1. To aid investigators in the planning of and preparation for their center-related research, by consulting on epidemiologic, statistical and data management issues. From an epidemiological perspective, this includes consultation on the appropriate study design, data collection instruments, issues related to the identification and measurement of exposure, outcome and potentially confounding variables, and the issues of bias. From a statistical perspective this includes planning for approprate sample size and a priori identification of data analytic methods, consultation on the design of datacollection instruments and the appropriate media for data storage. 2. To aid investigators in the execution of their center-related research, by providing data-management services. The services include advice on interviewer training, data editing, data management software, analysis software, and computer hardware; the creation of computer databases and database interface systems; and trouble shooting for data management problems which may arise during the course of a study. 3. To aid investigators in the analysis of the data for center-related research, by consulting on epidemiological and statistical issues. Such consultations range from advice on design and statistical tests for animal and epidemiologic studies to sophisticated multivariate regression models such as Poisson, proportional hazards, and polychotomous logistic regression. Consultations will also be provided for methods for advanced statistical analysis, including the development of new statistical models, if required. Consultation on various methods of correction for measurement error will be provided. Finally consultation regarding inference will be provided.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Abstract: Approximately 15-20% of breast cancers have a triple negative phenotype (negative for ER and PR expression and lack ErbB2 overexpression) that correlates with aggressive cancer and limited treatment options. We have developed an in vivo screen for defining the role of specific kinases in tumorigenesis and metastasis of breast cancer cells. Triple negative and triple positive breast cancer lines were used for shRNA-mediated knock down of specific kinases. The genetically altered lines (expressing luciferase in addition to specific shRNA gene knockdown) are injected into the mammary fat pad of female SCID mice. Tumor growth and vascularization is monitored longitudinally over an 8 week period using a micro-probe ultrasound system. Metastasis is monitored by bioluminescence imaging. The assay provides an in vivo screen for analysis of proteins that control the growth, vascularization and metastasis of breast tumors. MAP3Ks are the first tier of kinases regulating the MAP kinase signaling pathways that lead to the activation of the MAPKs ERKl/2, p38, JNK and ERKS. MAPSKs control expression of genes important for regulating the cell cycle, cytokine and protease expression and apoptosis. In a screen of 9 MAP3Ks, MEKK2 was identified as a key regulator of metastasis using MDA-MB-231 (triple negative basal) and BT474 (triple positive luminal) breast adenocarcinoma cells in the in vivo tumorigenesis assay. MEKK2 is a MAP3K that regulates the activation of the JNK and ERK5 pathways via activation of MKK7 and MEKS. We have shown that MEKK2 expression is required for EGFR (ErbBI) and ErbB2/Neu activation of ERKS in MDA-MB-231 and BT474 cells, respectively. Our hypothesis is that the MAP3K MEKK2 functions as a critical signaling node within the cell signaling network stimulating tumor growth and metastasis in response to ErbB and possibly other tyrosine kinases. The goal of this proposal is to genetically define the role of MEKK2 in triple negative breast cancer tumor growth and metastasis and to develop a MEKK2 small molecule inhibitor. Specific aim 1 involves defining the role of MEKK2-MEK5-ERK5 signaling in tumorigenesis and metastasis of triple negative breast cancer cells using the in vivo xenograft assay. In specific aim 2, we propose to elucidate the mechanism by which MEKK2 gets activated by ErbB1/2 using MEKK2 mutants in biochemical and cell-based activation assays. In specific aim 3, a small molecule biochemical screen will be developed to identify compounds that specifically inhibit MEKK2 kinase activity. MEKK2 inhibitors will be tested for MAPK pathway specificity in cell-based assays and profiled for specificity against the kinome. In future studies, these MEKK2 inhibitors will be tested for anti-tumor efficacy in genetically engineered mouse models (GEMMs) of breast cancer.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The long-term objective of the proposed work is the elucidation of the mechanism of DNA replication in animal mitochondria, and its relationship to mitochondrial mutagenesis and human disease. A combined approach of current methods in biochemistry and molecular genetics is being pursued to study the mechanism, structure and physiology of the major replicative enzyme in mitochondria, DNA polymerase y (pol y), and its functional interactions with proteins at the mitochondrial replication fork. Structure-function studies of pol y will involve comparative kinetic and physical analyses of native and altered forms, to continue to elucidate the role of the small subunit in enzyme function, and to dissect functional domains in both the catalytic and accessory subunits. Mutational studies will focus on elucidating the roles of the spacer region of the catalytic core, and physical analyses will map subunit contacts. Physiological studies will focus on expanding the development of a transgenic fly model to examine the relationship between pol y function, mitochondrial DNA replication fidelity, aging and disease. A novel recombinational knock-in approach will be taken to introduce and study several human-disease-related alleles of pol y in the context of mitochondrial biogenesis. The control of animal cell reproduction during normal development, and the loss of control during cancerous development, is of central importance in the processes of human growth, aging, and disease. Mitochondrial biogenesis proceeds in parallel with cell proliferation, but it is neither tightly coupled to mitochondrial DNA replication nor to the cell cycle. Nevertheless, because both the DNA content of the mitochondrion and the number of mitochondria in cells remain relatively constant, specific regulatory mechanisms are likely required to couple mitochondrial DNA replication and biogenesis to nuclear DNA replication and cell division. A detailed analysis of the key enzyme involved in mitochondrial DNA replication, DNA polymerase y, will represent a major contribution toward an eventual understanding of mitochondrial biogenesis and function in normal and diseased tissues. ! A variety of mitochondrial DNA diseases have recently been documented. This, and an increased recognition that antiviral and anti-tumor drugs frequently affect mitochondrial DNA function, and in particular, the activity of pol y, demonstrate a critical need for an in-depth understanding of this essential cellular DNA polymerase, and other proteins that function at the replication fork.
|
{
"pile_set_name": "NIH ExPorter"
}
|
ABSTRACT Emerin is an integral membrane protein of the inner nuclear envelope (INE) that binds to various nucleoskeletal partners and is a critical actor for the maintenance of the nucleus architecture and for nuclear mechanotransductions in response to forces. When mutated or absent, emerin causes Emery-Dreifuss muscular dystrophy (EDMD), an envelopathy whose underlying mechanisms and muscle specific effects are not fully understood. In particular, how emerin participates in molecular scaffolding at the INE and helps protect the nucleus against mechanical strains has remained largely elusive. As we have shown recently, using state-of-the-art optical microscopy, this is because the spatial organization of emerin and its mechanotransducing functions are modulated on distances of just a few nanometers at the INE, a length-scale inaccessible by conventional microscopy imaging techniques. Defining the pathogenesis of EDMD and other envelopathies, therefore demand new approaches that can establish the nanoscale structural organization of the INE while simultaneously modulating the mechanical landscape of nuclei in intact cells. Here, we propose an innovative integration of super-resolution and single molecule optical microscopy, nuclear biomechanics, biochemistry and quantitative biophysical analyses: (i) to establish the structural organization and the mechanotransducing functions of emerin at the nanoscale in human cells and (ii) to uncover the mechanisms by which its mutation results in abnormal nuclear mechanics in EDMD. Building on a large set of preliminary data with mutated emerins that localize correctly to the NE but induce EDMD, we hypothesize that the nanoscale oligomerization of emerin is directly coupled to its mechanotransducing functions and is further regulated by competitive interactions with various nucleoskeletal niches. We also hypothesize that defective nuclear biomechanics stem from dysregulated emerin oligomerization and, consequently, defective organization of structural niches at the INE. These hypotheses will be tested in two aims. In Aim 1, we will determine how nucleoskeletal niches differentially enriched in key emerin binding partners modulate the diffusion dynamics and the oligomeric state of wild-type emerin and a variety of EDMD-inducing emerin mutants at the INE of rescued emerin-null cells from human EDMD patients. This will be done using multi-parametric super-resolution microscopy, single molecule tracking and biochemical assays. In Aim 2, we will define the functional roles of emerin as a key nuclear envelope mechanotransducer in the context of EDMD by establishing how changes in the nanoscale distribution and oligomerization of wild-type emerin or emerin mutants dictate the normal or pathogenic mechanical responses of cell nuclei to increasing forces. This will be achieved using cell micropatterning approaches that controllably modulate the mechanical landscape of nuclei directly in cells. Together, this research project will greatly advance our fundamental understanding of mechanotransduction processes at the NE of human cells and will provide a completely new outlook on the function of emerin and the pathogenesis of EDMD. This work will also have a tangible impact on the vast array of nuclear envelope disorders by significantly improving our understanding of the diseases and by providing novel targets to develop therapies for patients affected by these pathologies.
|
{
"pile_set_name": "NIH ExPorter"
}
|
PROJECT SUMMARY Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema are lacking, presenting a critical barrier to improving patient prognoses after TBI. The objective of this proposal is to test the overarching hypothesis that generation of neutrophil extracellular traps (NETs) initiates a detrimental cascade that culminates in neurological deterioration after TBI. Specific Aim 1 will test the hypothesis that TLR4 activation mediates NET formation after TBI. Proposed mechanistic studies will demonstrate a key regulatory role for activation of the TLR4 signaling pathway in the formation of NETs after TBI. Specific Aim 2 will test the hypothesis that peptidylarginine deiminase 4 (PAD4) promotes cerebral edema after TBI. Proposed mechanistic studies will use genetic and pharmacological approaches to implicate PAD4, a mediator of TLR4-induced histone hypercitrullination in human and mouse neutrophils, in NET formation and neurological injury after TBI. Specific Aim 3 will test the hypothesis that degradation of NETs improves neurovascular function after TBI. Proof of concept studies will demonstrate that targeted degradation of NETs prevents cerebral microthrombus formation, leading to improved cerebral recirculation and reduced edema after TBI. These findings will provide the rationale for clinical repurposing of recombinant human DNase I (rhDNase1), a safe, FDA-approved therapeutic in widespread clinical use for non-neurological diseases, in the management of acute TBI patients. Expected outcomes of the proposed research include the identification of NETs as critical initiators of acute cerebrovascular dysfunction after TBI. In addition to providing a mechanistic explanation for the deleterious effects of neutrophils after acute injury, our studies will establish a critical framework for the development of targeted therapies to improve TBI outcomes. .
|
{
"pile_set_name": "NIH ExPorter"
}
|
The Given Institute of Pathobiology proposes to continue its program of advances in cancer seminars and workshops in techniques commonly used in cancer research. As in the past year, the Institute will offer two seminars for approximately 100 participants each and two laboratory workshops for 20 participants each. The subjects selected for 1975-76 include a general survey of advances in cancer biology and a seminar of herpes virus. The laboratory workshops will be on in vitro assays for transformation and on the identification and isolation of messenger RNA.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Speech sound disorders (SSD) are the most prevalent type of communication disorder in early childhood and often place an individual at risk for later academic difficulties. Individuals whose SSD persists past 8 years of age are at highest risk for poor long-term social-emotional, academic, and vocational outcomes. To date, there have been no large prospective studies to identify genetic, hormonal, and behavioral risk factors for persistent SSD so that children at greatest risk may be identified and treated early with interventions to prevent later adverse effects. The present proposal is a continuation of a 25 year genetic study of SSD (A Familial Study of Severe Phonology Disorders; NIDCD grant number DC000528) that has identified risk genes for SSD and co- morbid language impairment (LI) and reading disorders (RD). We found a higher prevalence of the most severe forms of SSD in males compared to females. Genes identified in our prior work regulate estrogen levels involved in early brain development, which may account for gender differences in gene expression. In the proposed project we will explore hormonal differences in children with SSD as a potential biomarker to identify children at greatest risk for persistent SSD. Predictive models for persistent SSD will be built from risk genes, hormonal biomarkers, and five behavioral endophenotypes: deficits in speech motor control, phonological memory, phonological processing, speeded naming, and vocabulary. Three hundred children with early SSD will be examined for all factors at 4-6 years of age and again at 8-10 years of age. Findings will reveal predictors of long-term problems to which individuals with early SDD are vulnerable, identify risk factors, and determine deficits to target in early interventions to insure more favorable educational, vocational, and behavioral outcomes.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Necroptosis is a newly discovered cell death pathway. Regulated by receptor-interacting protein kinase (RIP)1 and RIP3, necroptosis involves the purposeful disruption of the cell membrane by the effecter molecule MLKL. Necroptosis is inflammatory due to the release of cytoplasmic components that act as alarmins. Necroptosis is thought to amplify and promote inflammatory circles that contribute to chronic disease. What role necroptosis plays during aging is unknown. For example, does it contribute to inflamm-aging? Pore-forming toxins produced by Streptococcus pneumoniae and other airway pathogens have been shown to trigger lung cell necroptosis and this is responsible for much of the injury that is observed. The elderly are in particular vulnerable to pneumonia, with lower respiratory tract infections being the 4th leading cause of death in those ?65 years of age. Thus, inhibition of necroptosis is potential way to protect vulnerable individuals, such as the elderly, from the lung damage that occurs during bacterial pneumonia. We hypothesize that cell death by necroptosis increases with advanced age and this contributes to inflamm- aging. Also, that blocking necroptosis can protect the elderly from lung injury during pneumonia. Herein, we will leverage our expertise on aging, necroptosis, and bacterial pneumonia to test these hypotheses and improve our understanding of necroptosis and its impact during aging. We will: AIM 1. Determine the role of necroptosis on inflamm-aging and age-related decline in function. We have mice deficient in RIP3 and MLKL that cannot undergo necroptosis. We will compare pro-inflammatory cytokine and alarmin profiles in serum from WT, heterozygote, and KO mice at 6, 14, and 24 months of age. We will also examine aged WT mice treated for 7 days with two different necroptosis inhibitors. For all mice, we will examine the activation status of NFkB and MAPK in the thymus, lungs, heart, spleen, liver, kidney, brain, and visceral adipose by western and in immune cells (monocytes, B cells, T cells) by flow cytometry. We will also longitudinally measure activity, gait, and muscle strength to learn if blocking necroptosis impacts health status. AIM 2. Determine if blocking necroptosis protects aged animals against pneumonia. Alveolar macrophages and bone marrow derived macrophages from 6, 14 and 24 month old mice will be tested for their propensity to undergo necroptosis following exposure to the pore-forming toxin pneumolysin. Different aged WT, heterozygote, and MLKL KO mice, along with WT mice treated with necroptosis inhibitors will be intratracheally challenged with pneumolysin or infected with S. pneumoniae. Lung damage and disease severity will be assessed by measuring inflammatory cytokines, pathology, and bacterial burden, respectively. This proposal is in response to PAR-14-191:T1 Translational Research: Novel Interventions for Prevention and Treatment of Age-Related Conditions. We will determine the contribution of necroptosis to inflamm-aging and learn if blocking necroptosis protects against inflamm-aging related decline and pneumonia.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Clinical laboratory data displays organized by physiologic system or concept hierarchies may improve the speed and/or accuracy of clinical decisions as compared with displays organized by laboratory section. Nonmedical cognitive analysis studies indicate that graphical representation of data is associated with improved decision making in comparison with tabular numerical data, particularly in time-pressured situations. We hypothesize that identification and explicit graphical representation of important temporal relationships in clinical laboratory data will improve the ability of clinicians to reach decisions rapidly and correctly. We have developed a framework for identifying statistical patterns in timeseries data and temporal relationships between those patterns. We propose to 1) incorporate our framework into a problem-oriented display that prioritizes and visualizes clinical laboratory data adaptively based on types of temporal patterns in the data, 2) conduct patient case simulations in which clinician subjects access clinical laboratory data using traditional, problem-oriented, and temporal data-driven displays, and 3) evaluate the efficiency and accuracy of decision-making by clinicians under these simulated case conditions with mild time pressure, using "think aloud" techniques in which clinicians are video- and audiotaped during decision-making. The influence of these three user interfaces on decision-making will be evaluated by the accuracy of orders in comparison with an expert clinical gold standard, the relative proportions of information acquisition vs. information evaluation cognitive steps during case analysis, the total cognitive steps (cognitive load) required for case disposition, and the total number of screens and data elements viewed. We anticipate that the problem oriented display will support improved clinical decision-making through increasing the efficiency of information gathering; the temporal data-driven display may enhance decision-making further by focusing attention on, and directly visualizing, important relationships that would ordinarily have to be inferred.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Planning an efficacy trial of Flash-heated breast milk to decrease morbidity, improve growth, and reduce HIV transmission in HIV-exposed infants The World Health Organization recommends that HIV positive mothers in developing countries exclusively breastfeed for 6 months, and then stop once safe and nutritious foods are available. Many HIV- positive mothers in resource poor areas face a dilemma about how to feed their babies after they cease exclusively breastfeeding. On one hand, breast milk is richer in nutrients than most foods and contains antibodies and other protective components that protect the infant from common illnesses like diarrhea and upper respiratory infections. However, the likelihood of HIV transmission to the infant is higher with mixed feeds, i.e. when breast milk and other foods are both fed to the infant. Flash-heating expressed breast milk kills HIV and maintains most of the milk's nutritional and protective qualities. Previous research has also indicated that it can be acceptable and feasible for many mothers. Thus, heating expressed breast milk could be a safe and healthy way for an HIV-positive mother to feed her baby during this risky time. However, we do not yet know if this technique significantly improves the health of infants when compared to the alternatives of cessation of feeding any breast milk or providing mixed feeds. We propose to plan a clinical trial of heated breast milk to improve infant health in Tanzania. In the study we are planning, the primary aim will be to determine if infants whose mothers receive counseling on heat- treating expressed breast milk once other foods have been introduced are less likely to become infected with HIV and experience better growth and fewer days sick with acute respiratory infection or diarrhea, compared to infants whose mothers do not receive this counseling. Our secondary aim is to determine if local counselors can improve the prevalence and mean duration of exclusive breastfeeding and optimal complementary feeding by visiting HIV-positive mothers in their homes to give them education and support with healthful infant feeding practices. This portion of the study will examine a reduced home visit schedule to ascertain the success rate of the simpler, less expensive approach compared to previous studies of infant feeding counseling. Additionally, we will establish the cost- effectiveness of these two interventions, to determine if they should be implemented on a larger scale. The planning period will allow travel to Tanzania to define collaborative arrangements;finalize study design and sample size;choose study sites;attempt to secure funding;the design, translation and piloting of data collection instruments;application to US and Tanzanian IRBs;and plan staff trainings, among other necessary tasks to plan to conduct a multi-site clinical trial in a developing country. PUBLIC HEALTH RELEVANCE: Safer infant feeding options for HIV+ women in developing countries are needed because mixing complementary foods with breastfeeding after 6 months increases HIV transmission and stopping breastfeeding altogether often results in poor growth, illness and sometimes death. Heat- treating expressed breast milk kills the virus while preserving milk's nutritional and immunological properties, and thus could be a healthier method than other choices. We propose to plan a study to determine if babies of HIV+ mothers would have fewer infections, better growth and less HIV when their mothers are visited by women from the community to counsel them about heat treatment of breast milk and exclusive breastfeeding.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Although much progress has been made in determining the mechanisms of regulation of cyclin/cyclin dependent kinase activation, little is known about substrates for these protein kinase complexes. Still, it is considered likely that cyclins contribute to substrate selectivity for the different complexes, resulting in the specificity of e.g. Cln2/Cdc28 for G1/S events vs. that of Clb2/Cdc28 for G2/M events (note that the Cdc28 protein kinase catalytic subunit is the same in both cases). In order to examine this idea critically, and in order to begin to elucidate the mechanisms of action of cyclin-dependent kinases in triggering diverse cell cycle transitions, it is necessary to identify and characterize phosphorylation substrates of these complexes, to determine if any or all are specifically phosphorylated by individual cyclin/Cdc28 complexes, and to determine the functional consequences of these phosphorylation events for cell cycle control. We are designing exp eriments t hat will utilize our newly developed MS approaches to assist in the identification of these potentially important phosphorylation substrates.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Populations of African ancestry have greater bone strength and lower osteoporotic fracture risk than other ethnic groups. Although genetic factors are recognized as the major determinants of bone strength and osteoporosis risk, surprisingly little is known about the genetic determinants of skeletal health in African populations. We are proposing a comprehensive genetic epidemiologic study of the bone strength phenotype within extended families of African origin. Its long-term goals are to detect, map and characterize genes influencing variation in bone related traits in a unique Afro-Caribbean population that has remarkably high bone mass. The proposed pilot project is the first-step towards achieving these long-term objectives. For this pilot project, we will recruit 250 individuals belonging to extended families of African ancestry. Families will be identified and recruited through the 40+ year old participants (probands) in our population-based Tobago Bone Health Study. All first-, second- and third-degree relatives of the proband and the proband's spouse who are aged 20+ years will be recruited. Information on family relationships, medical history, medication use, and environmental risk factors such as diet, smoking, alcohol use, and physical activity will be obtained from each family member. Family members will also undergo a comprehensive musculoskeletal evaluation including: measures of bone mass at several skeletal sites; femoral structural geometry; anthropometry; appendicular skeletal muscle mass; and muscle strength. Quantitative genetic methods will be used to estimate heritabilities, the effects of environmental covariates for each phenotype, and genetic correlations among phenotypes. Finally, we will create a biological specimen repository for future genetic studies (i.e., genome-wide linkage and family-based association analyses), and for subsequent proposals to measure biochemical indices of bone modeling/remodeling, markers of mineral metabolism, and growth factors. This pilot project will provide essential preliminary data to support a largerscale proposal to enroll additional families, conduct genome-wide linkage analyses to detect and map genes influencing bone related phenotypes, and investigate possible gene- gene and gene-environment interactions in families of African ancestry. The identification of these genes will likely yield fundamental insight on bone biology and may lead to the development of novel approaches to the diagnosis, treatment, and prevention of osteoporosis.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objective of this project is to study immunologic cytotoxicity as a mechanism of discrete cellular lysis in cutaneous disease, with particular emphasis on antibody mediated mechanisms of lysis, especially antibody dependent cellular cytotoxicity (ADCC). The principle focus of this project is on ADCC as a mechanism of photosensitive papulosquamous cutaneous lupus erythematosus, attempting to explain the strong association of anti SSA antibodies to this clinical condition, by testing the hypothesis that SSA antigen induced by ultraviolet light on keratinocyte cell membranes binds specific anti SSA antibody, inducing cytotoxic damage to keratinocytes by lumphocyte and monocyte effectors via ADCC. The variable involved in expression of SSA and SSB on keratinocyte cell membranes will be tested and the binding of antibodies to SSA and SSB to purified antigenic components and to the molecular complex containing both antigens will be analyzed. Using this information, anti SSA and anti SSB dependent keratinocyte lysis will be analyzed in vitro and in vivo in different models using cultured human keratinocytes as target, human skin explants as targets, human skin grafted onto the nude mouse as a target, or guinea pig skin as a target. Relevant models of keratinocyte damage by anti SSA will be used to test the mechanisms of action of corticosteroids, antimalarials, dapsone, retinoids, antimetabolits, and antioxidants as useful or potentially useful drugs in the treatment of cutaneous lupus. Another important set of aims of this project involves the study of the variable susceptibility to cytotoxicity of different cutaneous targets (keratinocyts, melanocytes, endothelial cells, fibroblasts). This portion of the study will focus on antioxidant defenses of cutaneous targets, how differences in these affect the susceptibility of these cells to immunologic lysis and how therapeutic antioxidants may affect these targets in skin disease. Finally, we will begin pilot projects to study antibody dependent cytotoxicity in other skin diseases such as pemphigus vulgaris, bullous pemphigoid, alopecia areata, and vitiligo.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Breast cancer is the most prevalent non-skin cancer in women in the US. To increase the early detection of breast cancer, annual screening mammography has been recommended for asymptomatic patients. However, mammography is not without limitations. The superposition of glandular tissue is an inherent consequence of the two dimensional nature of mammography, and may result in the masking of lesions of interest (reducing sensitivity) or the false appearance of overlapping normal tissues as lesions (reducing specificity). Digital tomosynthesis of the breast is a novel x-ray based imaging technique being investigated to replace mammography for the early detection and diagnosis of breast cancer. Tomosynthesis is based on the concept of limited angle computed tomography, in which projections of the imaged object acquired from a limited angular range give enough information to partially reconstruct that object in three dimensions. Reports indicate that tomosynthesis reduces callback rate (increasing specificity) and increases detection rate (increasing sensitivity) compared to mammography. However, in current implementations of breast tomosynthesis, the breast undergoes the same vigorous compression as that used in mammography. It has been shown that the pain resulting from this vigorous breast compression during mammography is an important factor in women not undergoing the recommended annual screening mammography. This reduction in screening adherence results in an increase in breast cancer mortality and in a reduction in treatment options, yielding a higher number of mastectomies as opposed to breast conserving surgeries. The objective of this research project is to develop and test new image acquisition and processing techniques that will allow for the acquisition of breast tomosynthesis images with a substantial reduction in the amount of breast compression used with no loss in image quality or increase in radiation dose. For this, we will (1) develop a method to reduce the impact of x-ray scatter on image quality; (2) develop new image acquisition techniques for reduced compression tomosynthesis that result in the same radiation dose and image noise levels as standard tomosynthesis; (3) compare the image quality between standard tomosynthesis and reduced compression tomosynthesis performed with the techniques developed in this project. Successful completion of this project will result in the ability to perform breast tomosynthesis imaging with substantially reduced breast compression levels, with no increase in radiation dose, and no loss in image quality and tissue coverage. This will result in a reduction in the pain associated with breast cancer screening, resulting in an increase in screening adherence by women, which will decrease breast cancer mortality and increase the number of cases in which breast conserving surgery can be performed.
|
{
"pile_set_name": "NIH ExPorter"
}
|
In this Phase II project, the goal is to continue development and validate the radiation toxicity (RadTox) diagnostic test. We will also explore if gene expression in blood can be used to predict radiation sensitivity. In our Phase I study, gene expression based biomarkers were identified, the DxDirect based assay was developed, and the prototype predictor algorithm was developed. In Phase II the sample size will be increased to at least 500 patients, confounders will be identified, the gene expression assay will be further developed and validated, and the locked assay will be transferred to DxTerity?s CLIA/CAP laboratory for initial commercialization. We will also begin Quality System Regulation (QSR) compliant product development. During this Phase II SBIR contract, we will complete Phase 0 and Phase 1 of product development. DxTerity?s long term intention is to submit the assay for eventual FDA clearance with the intention of being a product line upgrade to DxTerity?s REDI-Dx: High Throughput Biodosimetry assay.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Addiction is a tremendous health and financial burden on our society. A growing literature indicates that norepinephrine in the brain plays a key role in stress-reward interactions that may mediate key behavioral responses to drugs of abuse. A previously unappreciated group of noradrenergic neurons in the field of addiction, cells that project through the ventral noradrenergic bundle (VNAB), are thought to supply the key norepinephrine. The primary target of the VNAB in the brain is a group of nuclei referred to as the extended amygdala. In the previous funding period, we identified actions of each of the major classes of noradrenergic receptors on excitatory synaptic transmission in the bed nucleus of the stria terminalis, a major component of the extended amygdala. Here, we propose experiments to assess molecular mechanisms involved in these actions, and to begin to place these actions in the context of microcircuitry within the extended amygdala. Further, we propose to examine whether overlapping populations of neurons in the extended amygdala are activated by drugs of abuse and stressors, and whether this activation is regulated by noradrenergic ligands. In total, the proposed work will begin to define specific mechanisms likely to play key roles in stress-induced reinstatement of drug seeking behavior, thus providing new potential opportunities for therapeutic development.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Pediatric brain tumors are the most common malignant solid tumors in children. Despite modern treatments having increased survival, current therapeutics often carry debilitating side effects with them, including lifelong intellectul and neurological disability. Because of this, there is a pressing need for novel therapeutic approaches. While transforming growth factor-beta (TGF-) is one of the most well-studied immune molecules in cancer biology, in regards to pediatric brain cancer, precious little is known. We recently showed that genetic blockade of T cell TGF- signaling promotes CD8 cytotoxic T lymphocyte (CTL)-mediated anti-tumor immunity in the smoothened (SmoA1) mouse model of medulloblastoma (MB). Furthermore, inhibiting T cell TGF- signaling led to generation of CD8+ short-lived effector T cells (SLECs) that were efficient tumor cell serial killers. These results uncover a cellular immune mechanism whereby TGF- signaling blockade licenses CD8 SLEC-CTLs to kill pediatric brain tumors. The central theme of this revised exploratory grant application is to develop an experimental pharmacological approach for the treatment of MB. Specifically, we seek to test whether nanoparticle-based blockade of TGF- signaling in the key cellular mediator of anti- tumor immunity, the CD8 T cell, is a viable MB therapeutic approach. To achieve this goal, we will: 1) test whether CD8 targeted nanoparticle inhibition of TGF- signaling in peripheral T cells will prevent or treat established MB in SmoA1 mice, and 2) elucidate the mechanism of CD8 SLEC-CTL activity in nanoparticle-treated CD8 T cells. Through a collaborative effort, we have already developed CD8- targeted nanoparticles consisting of the biodegradable polyester, poly(ethylene glycol) and poly(lactic-co-glycolic) acid (PEG-PLGA), encapsulating the small molecule TGF--Smad 2/3 signaling inhibitor (SB-505124) and the non-toxic fluorescent tracer, Coumarin-6 (C6). In Specific Aim 1, we will utilize this pharmacologically-relevant method to target TGF- signaling in CD8 T cells in SmoA1 mice. Both disease prevention and active treatment study arms will be carried out. For Specific Aim 2, CD8 T cells will be isolated from SmoA1 animals treated with C6 or C6/SB nanoparticles and tumor cell killing will be read-out by an established CTL assay. Western blot analysis will be performed on isolated CD8 T cells from these animals to verify TGF- signaling inhibition. Immunophenotyping will be carried out to determine if CD8 T cell TGF- signaling blockade promotes conversion to SLEC-CTLs. We hypothesize that nanoparticle-mediated TGF- pathway blockade in CD8 T cells will prolong survival in a pre-clinical animal model of pediatric brain cancer by promoting the SLEC-CTL anti-tumor immune response.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The section works on a) the interaction of biologically important polysaccharides with antibodies; b) the structure and nature of antibodies; c) the preparation of monoclonal immunoglobulins to specific determinants.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objective of this work is to study the role of thyroid hormone binding proteins in mediating the toxic effects of certain halogenated aromatic hydrocarbons of environmental importance. Current interest is in the binding proteins specific for thyroxine (T4). Prealbumin (TBPA) is a major thyroxine binding protein in blood which has been proposed as a model for the thyroxine nuclear receptor in tissue. Molecular interactions of TBPA with the dioxins, furans and polychlorinated biphenyls (PCBs) have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by experimentally measuring the binding affinities of soluble derivatives of those structures, and the results are in good agreement with prediction. The binding model can account for the requirement for lateral halogens and an approximately rectangular molecular shape in toxicity. Similar studies with the thyroxine nuclear protein solubilized from rat liver tissue also show competitive binding interactions and with similar binding specificties. A soluble dioxin approximate isostere shows a remarkably high affinity (half-maximal of 15 pM) for the nuclear receptor (compared to a half maximal of 15 nM for T4). Thus the nuclear receptor affinity has the expected sensitivity for possible involvement in toxicity. Dose-dependent regulation (increase) of the T4 nuclear receptor number by dioxin was demonstrated and suggest a possible mechanism for potent and persistent expression of thyroid hormone activity which could result in toxicity.
|
{
"pile_set_name": "NIH ExPorter"
}
|
DESCRIPTION: Using genetic and biochemical approaches, Dr. Brody proposes to study the role of the T4-coded asiA gene. The 10kDa asiA protein was shown by Audrey Stevens to bind to the sigma-70 subunit of E. coli RNA polymerase, hinder sigma-70 interaction with core enzyme, resulting in inhibition of sigma-70 dependent transcription. Dr. Brody's laboratory has recently identified, cloned, and sequenced the asiA gene, and has overproduced the protein in E. coli. Recent experiments from Brody's lab indicate that the asiA gene is involved in 1- redirecting the E. coli RNA polymerase from T4 early to middle promoters 2- positively activating, in conjunction with the T4 motA protein, E. coli sigma 70 RNA polymerase to form open complexes at middle promoters and 3- possibly aiding T4 sigma 55 in interacting with core RNA polymerase for transcription of the T4 late genes. Recently, Brody's laboratory has been successful in purifying large quantities of active asiA. He now proposes: 1- experiments to investigate the assembly and function of the T4 middle transcription complex. To that end he will use gel filtration and native gel electrophoresis to study the assembly of the complex and reversible protein-protein crosslinking agents to probe for protein contacts in the complex. DNAse I, OH radical and potassium permanganate footprinting of DNA will be used to understand how binding of the various proteins affect each others binding to the promoter. 2- genetic experiments to look at the possible existence of interaction between MotA and asiA and at the interaction of sigma 70 with either T4- coded protein. Sigma 70 deletions and point mutations will be used to map the interaction with asiA. Mutants in sigma-70 resistant to asiA inactivation will be isolated. Physical interactions will be probed by native gel electrophoresis, gel filtration, precipitation with monoclonal antibodies and protease protection experiments. 3- investigate the role of asiA in shutting off early transcription in vivo. 4-investigate the role of asiA in the late transcriptional switch in vitro. 5- determine the effect of gp asiA on sigma factors from many microorganisms to see whether gp asiA could be a useful, specific antibiotic.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Pancreatic cancer accounts for 5% of cancer deaths in the United States and is the fourth leading cause of cancer mortality. According to the SEER Cancer Statistics Review, it is estimated that in 2009 there will have been over 42,000 new cases of pancreatic cancer and over 35,000 deaths. Current treatment options are of limited benefit with a 5-year survival rate following diagnosis of less than 5%. The current standard-of-care therapy, gemcitabine, only improves survival by a few weeks. It is clear that more effective therapy for the treatment of pancreatic cancer is needed. Ultrasound-enhanced drug delivery is an active and promising area of research. Ultrasound has been demonstrated to enhance vascular permeability and drug penetration into tissue, primarily due to mechanisms related to cavitation. Ongoing research efforts (including preliminary data from our lab presented in this proposal) have identified ultrasound mechanism and parameters that are likely to be effective in vivo. Several in vivo studies have been performed in various xenograft and syngenic autograft animal models that have demonstrated that ultrasound enhanced drug delivery is effective in decreasing tumor size and increasing survival duration;however, these tumor models, especially for pancreatic cancer, have been criticized for being unrealistic and not representative of the true in vivo environment seen in the human disease. In this proposal, we believe that we have developed a study that includes rigorous fundamental science, but also is rapidly translatable. The attractiveness of the strategy in this proposal is that it utilizes a chemotherapeutic agent that is the current standard of care (gemcitabine) along with focused ultrasound technology that is currently available and readily implementable to rapidly translate these results into human clinical trials. In addition, it brings for the first time to the study of ultrasound-enhanced drug delivery a unique and realistic animal model (KPC mice), which will provide much more realistic data to evaluate the potential for clinical translation. The overall aim of this proposal is to investigate whether ultrasound can enhance targeted drug penetration into an in vivo pancreatic tumor and improve survival duration. We believe that the successful accomplishment of the specific aims of this proposal will be a major step toward applying this promising approach to human patients who are suffering from pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer accounts for 5% of cancer deaths in the United States and is the fourth leading cause of cancer mortality and current treatments are essentially ineffective. The overall aim of this proposal is to investigate whether ultrasound can enhance targeted drug penetration into an in vivo pancreatic tumor and improve survival duration. We believe that the successful accomplishment of the specific aims of this proposal will be a major step toward applying this promising approach to human patients who are suffering from pancreatic cancer.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objectives of the CPCRA Clinical Trials Unit (Community Programs for Clinical Research on AIDS) are: to conduct clinically relevant research in the prevention and treatment of HIV disease and its complications;to involve in clinical trials a demographically, geographically, and socio-economically diverse population of individuals infected with HIV or at risk of infection;and to carry out this research agenda in close collaboration with community members who are themselves infected with or affected by HIV. The CPCRA CTU will make significant contributions to the INSIGHT and HIV Prevention Trials (HPTN) networks, both in enrollment and in scientific expertise. Through INSIGHT, the CPCRA CTU will contribute to multiple, randomized clinical trials in order to help determine the optimal clinical management for persons who are HIV+. These trials include studies of those who are: highly-antiretroviral (ARV) experienced and for whom virologic suppression cannot be achieved and maintained;ARV-naive, with advanced HIV disease and presenting for care with an opportunistic infection;co-infected with HIV and hepatitis virus;or at moderate-to-high risk of cardiovascular disease. Through the HPTN, the CPCRA CTU will contribute to trials examining both behavioral and therapeutic interventions with behavioral and biologic outcomes, seeking to reduce HIV transmission and HIV transmission-risk behavior. Targeted populations include those who are HIV+, as well as those who are HIV- and at-risk for seroconversion, such as injecting-drug and cocaine users and others at risk for seroconversion through sexual contact. The Executive Office of the CPCRA Clinical Trials Unit, located at the Veterans Affairs Medical Center in Washington DC, is an off-campus affiliate of the applicant institution, The George Washington University. The Principal Investigator and Executive Office staff provide oversight, central coordination, training and education, technical assistance, and regulatory support for its 137 CRSs, organized by region into 23 Site Coordinating Centers (SCCs) in the United States, Brazil, Canada, Peru, and South Africa. These sites have in care a cumulative, demographically diverse patient base of over 152,000 persons with HIV/AIDS. HIV is a major public health problem around the world. It is important to find better ways to use the medicines that we have to treat HIV, so that people who are infected can live longer and healthier lives. It is also important to find better ways to stop the spread of HIV by doing studies with people who have HIV infection and people who don't have HIV but who are at risk for getting HIV infection. ADMINISTRATIVE COMPONENT:
|
{
"pile_set_name": "NIH ExPorter"
}
|
The systematic wrapping of an axon by insulating myelin sheaths is a remarkable event in the development of the vertebrate central nervous system. Despite the importance of myelin for the rapid conduction of action potentials, little is known about its molecular mechanism. We have been using the rat optic nerve as a simple model system to study myelination. When purified rat retinal ganglion cells are cultured together with purified oligodendrocyte precursor cells (OPCs) little myelination occurs. However, when the pharmacological inhibitor of gamma-secretase, DAPT, is added to the culture medium, robust myelination occurs within 3 days, providing us with a simple culture system to study myelination. In this application, we will focus on the hypothesis that CNS myelination is normally controlled by a gamma-secretase substrate. First, we will test whether DAPT promotes myelination in culture by inhibiting gamma-secretase activity in neurons or in oligodendrocytes and investigate whether gamma-secretase activity within the developing optic nerve normally helps to control myelination. Second, we will test 3 specific candidate signaling pathways, known to be regulated by gamma-secretase, that have previously been implicated as potential controllers of myelination: the Jagged1-Notch1 pathway, Neuregulin-erbB4 pathway, and N-cadherin-mediated adhesion. Third, we will determine whether DAPT promotes myelination by enhancing local axon-glial interactions or by inducing oligodendrocytes to differentiate to a myelinating stage. We will perform time-lapse microscopy to ask fundamental questions about how oligodendrocytes myelinate axons. Finally, we will study the gene changes that accompany DAPT-induced myelination. Together, we hope that these experiments will provide a better understanding of the molecular mechanisms that control CNS myelination. Understanding how myelination is regulated may suggest new ways of enhancing remyelination after injury or diseases such as optic neuritis and Multiple Sclerosis.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The UNZA-Vanderbilt Training Partnership for HIV-Nutrition-Metabolic Research (UVP) continues a longstanding training collaboration of the University of Zambia School of Medicine/University Teaching Hospital (UNZA/UTH) and Vanderbilt University (VU) and its Institute for Global Health (VIGH). With PEPFAR's successes turning HIV into a chronic condition, many Africans are living full lives with HIV, but they are facing non-communicable diseases that come with lifelong antiretroviral therapy (ART), lifestyle changes accompany- ing the epidemiologic transition, and aging. Nutritional factors are central to many of these, especially in low- income countries, affecting pathogenic processes in the gastrointestinal tract, kidneys, nervous system, and cardiovascular system. UNZA-VIGH collaborations have discovered multiple nutritional influences on ART outcomes. A recently completed large-scale HIV-nutrition clinical trial (NUSTART) has built large specimen and data repositories that are available for analyses and long-term follow-up studies. UNZA has identified PhD training as crucial for advancing its institutional research capacity and academic leadership. UVP will support this by training UNZA PhD-level HIV research leaders in nutritionally- and metabolically related complications and comorbidities of HIV, while expanding UNZA/UTH's research training and investigative capacities. UVP will provide long-term research training for advanced UNZA trainees and junior faculty members, leading to 11 sandwich PhD degrees awarded by UNZA and undergirded by Vanderbilt didactic courses, research mentorship, and institutional resources. It will support innovative multidisciplinary mentored dissertation research focused on the key metabolic and nutritional challenges in long-term HIV care. The UVP proposal is distinguished by a 17-year AITRP partnership that has enabled 41 Zambians to obtain advanced degrees (mainly Master's) and has substantially facilitated many US grant-funded education and training efforts described within (AITRP, MEPI, ZEPACT, FICRS-F, Fogarty GHF). UVP will enhance the UNZA PhD Program by conducting in-country consultations, skill-building short courses, and faculty development workshops to strengthen PhD mentoring standards and assess measureable milestones. It will provide career development opportunities for research-focused UNZA faculty members via 4-month VU-based postdoctoral sabbaticals, to expand research collaborations between UNZA and VU investigators and to attract extramural research funding. We will document the program's long-term success by tracking major trainee outputs; providing ongoing skill-building opportunities for our AITRP alumni; conducting regular program evaluations; and engaging our AITRP alumni as active in-country instructors in ongoing Zam- bia-based trainings. UVP will strengthen UNZA's capacity to train future researchers, attract extramural research funding, and generate high-impact research outputs in a vital HIV research arena. Sustainabil- ity will be maximized by mentoring future mentors within all UVP activities.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Cellular identity is controlled by the selective expression of genes, a process determined by regulation of the open and closed states of chromatin-the complex of DNA and histone proteins. Histone post-translational modifications (PTMs) can alter the biophysical properties of chromatin and also selectively recruit o eject histone-binding proteins or readers, thereby regulating biological processes. Among the diverse substrate options for histone-modification, the highly charged nature of phosphorylation bears great potential to alter histone-histone and histone-reader molecular interactions. Indeed, paralleling many upstream kinase pathways, signaling to chromatin through histone phosphorylation serves as a rapid, reversible, and selective mechanism for the interpretation of signaling inputs leading to chromatin processes including control of cell cycle (Aim 1), rapid induction of transcription (Aim 2), and chromati structure, histone variant regulation, and oncogenesis (Aim 3). However, numerous fundamental issues concerning histone phosphorylation and its participation in chromatin processes remain unanswered. In Aims 1 and 2, we will test the hypothesis that diverse functions of histone phosphorylation-with a focus on transcription and cell cycl regulated processes-are defined and controlled by their association with other combinatorial histone modifications and the selective recruitment or ejection of readers. We propose an ambitious research plan, with a high likelihood of success and supported by preliminary findings and world class collaborators. We will assess how histone phosphorylation, acting together with other histone PTMs, can serve to instruct diverse functions including cell cycle regulation and activation of transcription. In aim 3, we propose the study of phosphorylation at histone variant-specific residues as a mechanism for signaling to chromatin at select genomic localizations, with functional consequences mediated by altered chromatin structure, nucleosome stability, and the binding of specific readers. Additionally, we propose to study oncogenic histone mutations, flanking key phosphorylation residues, and their disruptive effects on histone phosphorylation regulated processes that may drive oncogenesis, including dysregulated cell cycle and genome instability. Here, we embrace the complexity of histone encoded information, employing novel and cutting-edge techniques together with our expertise in chromatin biology to better understand the diverse functions of histone phosphorylation. The ambition of this research is the discovery and characterization of new regulatory processes and potentially druggable readers downstream of histone phosphorylation in the context of development, inflammatory transcription responses, regulation of the cell cycle, and oncogenesis with extreme relevance to human health and disease.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The 4th Annual Meeting of the International Cytokine and Interferon Society (ICIS) will be held in San Francisco, California at the Hyatt Regency Hotel from October 16 - October 19, 2016. This international conference will bring together leading investigators in the fields of cytokine signaling and biology, immunology, cancer research, metabolism, and infectious diseases. The Co-Chairs for this meeting are Dr. David Artis (Cornell University), Dr. John O'Shea (NIH), Dr. Erika Pearce (Max Planck); together, these scientists cover a broad spectrum of scientific expertise relevant to the interests of the ICIS, and have an excellent working relationship as a group. A major goal of the meeting will be to promote the interactions between scientists focusing on cytokine signaling and function in diverse areas of biology, such as host-microbiota interactions, innate immunity, host defense, immune regulation of whole body metabolism, cellular metabolism in immune cells, primary immunodeficiencies, and epigenetics ? and how these translate into emerging therapies. Another goal of this meeting is to facilitate interactions between young investigators and trainees with established researchers in the interferon and cytokine field. Outstanding junior investigators, postdoctoral researchers, and graduate/medical students will be encouraged to participate, and awards will be given to young researchers in each of these categories, as described in the body of this proposal. In addition to approximately 34 invited speakers (some slots remain open for late-breaking speakers) scheduled for Plenary Sessions and Symposia, a number of abstracts submitted by registrants will be selected for oral presentations in Special Topics Sessions. Particular attention will be paid to giving junior investigators an opportunity to present their work during these sessions. Up to 300 participants are welcome to present a poster and will be given the opportunity to discuss their work during their poster session. The program includes scientists from academic institutions, as well as from biotechnology and pharmaceutical companies. We have paid special attention to ensure a program that is well-balanced by gender, ethnicity, seniority and geographic location. A special effort will be made to support the career development of under-represented minorities and women, and an important part of the 2016 meeting is to have 2 workshops and a special reception exclusively for trainees and young (1st year) faculty, designed to foster these interactions. It is the firm belief of the Co-Chairs and Scientific Organizing Committee (composed of 17 scientists from 8 countries including 7 females and two URMs) that, by bringing together leaders, junior investigators, and trainees in these diverse areas of cytokine research, this meeting will inspire important new avenues of investigation and will be of great benefit to the career development of promising young investigators and trainees in the cytokine field.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The aim of the research program proposed here is to explore how established drugs influence solute and water transport across simple epithelia,: such as capillary endothelium, peritoneal mesothelium, amphibian bladder and lung, hamster yolk sac and renal tubules. The experiments are expected to clarify: (a) mechanisms of solute transfer across epithelial barriers, with special emphasis on diffusion; (b) the process of water transfer across epithelial barriers; (c) humoral and neural mechanisms that may control and regulate epithelial permeability in health and disease. In characterizing transport processes across epithelia, many different phenomena must be considered and, where appropriate, measured (e.g., the electrochemical gradient, unidirectional flux constants, tissue pool of transported solute, etc.). Furthermore it is essential to consider mechanisms that serve to minimize back-diffusion, notably the metabolic destruction of the solute, its sequestration by tissue binding sites or by specific drug receptors, and removal by diffusion and by bulk flow. Experiments in these areas are expected to generate information that will serve many practical purposes. For example, a useful method for detecting and evaluating local drug effects on the transport capacity of tissue capillaries has been developed. It will be exploited in laboratory animals to examine drugs used in the treatment of coronary ischemia (angina pectoris). Other studies are expected to clarify the renal toxicity of radiographic contrast agents and the modes of action of some teratogenic substances. Factors that influence acute desensitization of isolated tissues to directly acting agonists will also be examined.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Ecstasy (MDMA) use has increased sharply among youth in both the US and worldwide. Although the medical literature is replete with studies documenting serious physical consequences associated with ecstasy, little is known about the natural history of ecstasy use and its effects on behavior and mental health. The goal of the proposed research is to contribute critically needed epidemiologic information about the risk factors for becoming an ecstasy user, the patterns of ecstasy use, and its longer-term consequences. The study will also have broader implications for the description and prediction of illicit drug use patterns in general among college students. A longitudinal prospective study of a large sample of college students at the University of Maryland, College Park, a major public University with a diverse student body, will be conducted. The three specific aims of the project are to: 1) identify the predictors of onset of ecstasy use; 2) characterize ecstasy use patterns and develop models to better understand changes in ecstasy use; and 3) describe and predict the consequences of ecstasy use, among college students. A two-stage procedure will be used to recruit students into the study. First, a screening instrument will be administered to all incoming freshman via cooperation with the University's Orientation Office. Second, based on information from the screening, we will recruit 18-19 year old students who fall into three groups and will be eligible for longitudinal follow-up: 1) A "high-risk sample" of non-users of ecstasy at baseline who have used marijuana (Specific Aim# 1); 2) "Prevalent" cases, ecstasy users at baseline, who, in conjunction with incident ecstasy users from Specific Aim# 1 will comprise the sample to study ecstasy use patterns (Specific Aim# 2), and, 3) A "low-risk" sample of non-users of both marijuana and ecstasy at baseline, primarily for comparative purposes for Specific Aim # 3. These students will be assessed annually for three years with a face-to-face interview and semi-annually with mail-in questionnaires. Risk factors that are hypothesized to be related to the initiation of ecstasy use and changes in the pattern of use include family factors (e.g. family history and quality of relationships), social influences (e.g., peer influences, attendance at "raves"), personal characteristics (i.e., behavioral dysreguhtion/sensation-seeking), contextual variables and drug use history. The classes of consequences to be studied in the sample over time are: 1) alcohol and other drug dependence; 2) high risk sexual activity; 3) academic performance; and 4) mental health problems (i.e., anxiety and depression). This study will complement research about the neurobiological mechanisms of risks and consequences of ecstasy use, add to the existing body of knowledge on college drug use, and have important implications for the identification of persons at high risk for ecstasy use and those in need of prevention and early intervention services.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Project summary: The objective of the proposed research is to develop novel approaches and/or adapt currently available techniques for genetic modification of a variety of laboratory animal species. Currently, mice are the most common species of animal used in research. Their popularity derives from their small size, low relative cost to breed and maintain, short gestation, and large litter size, as well as the vast array of commercially-available reagents and technologies. One of the greatest advances in animal model development has been the generation of techniques for producing mice that express foreign DNA (transgenic mice, knock-in mice) or have a native gene deleted (knock-out, or gene-deficient, mice). A major drawback to using mice as animal models is that they often fail to reliably mimic human development or disease. However, many of the techniques used to modify the mouse genome have been difficult to adapt to non-rodent species or are cost prohibitive to attempt in other species. Several methods have been developed to overcome these obstacles, and several recent reports have described a highly successful method for generating gene deficient rats using zinc finger nucleases (ZFNs). Briefly, ZFNs are synthetic proteins consisting of an engineered DNA- binding domain fused to an endonuclease that induce double-stranded breaks in specific DNA sequences. The DNA breaks are repaired by host cell repair pathways, with a proportion of the repairs incorporating errors resulting in genetic mutations that often translate, in effect, to deletion of the targeted gene product. The overall goal of the project described here is to use ZFN technology in the development of reliable and cost-effective methods for producing genetically modified animals that is applicable across species. Sperm- mediated gene transfer (SMGT) will be used to deliver the ZFN to the developing embryo. Using this method, freshly isolated sperm will be incubated with DNA encoding the ZFN. DNA binds to specific proteins on the surface of the sperm and is transported intracellularly. DNA-laden sperm can then be used to fertilize ova in vitro or in vivo. This technology will be compared in two species, one rodent and one non-rodent, to demonstrate proof of concept and to generate genetically modified guinea pigs and sheep that are valuable models for human diseases. The specific aims of the project are to generate 1) guinea pigs deficient in one or more genes involved in the generation of immune responses and 2) sheep deficient in one or more genes involved in embryonic development of the cardiac and respiratory systems.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Project Summary/Abstract: We have recently developed open-reading-frame (ORF) phage display, a technology which has the potential to join yeast two-hybrid system and mass spectrometry as a major technology of functional proteomics. To explore the versatile applications of ORF phage display, we used a functional cloning strategy to isolate eat-me signals or phagocytosis stimulating molecules in retinal pigment epithelium (RPE) cells and identified 9 putative eat-me signals including tubby-like protein 1 (Tulp1) and tubby. Deletion mutations of the C-terminal 44 amino acids (aa) in tubby (tubby-DC44) and Tulp1 (Tulp1-DC44) associate with retinal degeneration with undefined mechanisms. Moreover, tubby-DC44 and Tulp1-DC44 abolish their stimulation of RPE phagocytosis. The long term goal of this project is to define the disease mechanisms of tubby and Tulp1 in retinal degeneration. The objective of this application is to elucidate the role of the highly conserved C- terminal domain of tubby and Tulp1 in RPE phagocytosis. The central hypothesis of this study is that tubby and Tulp1 are bridging molecules to facilitate RPE phagocytosis by simultaneously binding to Mer tyrosine kinase (MerTK) on RPE cells and the shed photoreceptor outer segments (POS) vesicles. This hypothesis will be investigated by characterizing the C-terminal domains of tubby and Tulp1 through vesicle pull-down assays and mutational analysis to map their minimum domains that bind to photoreceptor outer segments (POS). Moreover, the function of tubby and Tulp1 C-terminal domains will be defined by identifying their protein binding partners using the newly-developed ORF phage display technology. This study will not only elucidate the pathological mechanisms of tubby and Tulp1 C-terminal mutations, but will also help promote and disseminate the new technology of ORF phage display for its broad application as an efficient, sensitive, versatile and convenient technology of functional proteomics in biomedical research.
|
{
"pile_set_name": "NIH ExPorter"
}
|
This competing continuation proposal describes the "next steps" in a program of research initiated in 2003, entitled the Head Start REDI (Research based, Developmentally Informed) project. The REDI project was designed to enhance the impact of Head Start on child school readiness by promoting teachers' capacities to integrate empirically-based instructional strategies with their ongoing programming. Two domains of school readiness were targeted: 1) language development/emergent literacy skills, and 2) social-emotional competencies. The initial randomized trial (involving 356 children from 44 Head Start classrooms) demonstrated improvements in teaching quality in REDI classrooms, based upon observer ratings of language use, instructional support, and emotion coaching. In addition, children who received REDI showed enhanced vocabulary, emergent literacy skills, social competence, and learning engagement, and reduced aggression at the end of the Head Start year, relative to children attending "usual practice" Head Start classrooms. This proposal for continuation has two major aims. The first aim is to conduct follow-up assessments with children who participated in the initial trial to evaluate the long-term effects of the REDI program on child school adjustment in the later elementary years (grades 3 and 5.) In the context of this aim, we also plan to examine transactional influences over time between trajectories of skill gains in child language/literacy skills and social-emotional competencies, and to explore potential moderation of sustained program effects as a function of early elementary school context (i.e., instructional quality, classroom context, and teacher-student relationship quality). The second major aim of this proposal is to evaluate the added benefit of a parent-focused extension of the REDI program using a randomized controlled design with a new sample of 200 children attending Head Start classrooms in the original counties. Building upon the Head Start tradition of parent involvement, the goal of this parent-focused extension of REDI is to improve cross-setting support for child language and social-emotional skill development during the Head Start year and provide transition support for children as they move from Head Start into kindergarten. Longitudinal assessments of this new sample will extend over a three-year period (pre-test at age 4; post-test at the end of kindergarten, and follow-up assessment at the end of first-grade). Multi-method, multi-informant measures will be used to assess the impact of the parent-focused extension of REDI on children s oral language skills, emergent literacy skills, learning engagement, social-emotional competencies and behavior problems. We also will evaluate program impact on the targeted parenting practices and determine the degree to which they mediate child outcomes. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Children growing up in poverty are particularly likely to enter school without the language and social-emotional skills they need to adapt and achieve, placing them at risk for increasing delays in academic attainment, along with behavioral difficulties that have long-term deleterious effects. This research evaluates the short- and long- term impact of infusing "research-based" instructional strategies into Head Start programs in ways that support both teachers and parents, and that promote child language and social-emotional readiness skills, and thereby enhance child readiness for school and foster school attainment. The focus on evaluation and extension of a school readiness program targeted to poor children is highly significant. Results could provide improved strategies for intervening with such high risk populations. [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
This proposal sets the stage for clinical trials of gene therapy for hemophilia A. Here we concentrate on the use of adeno-associated viral (AAV) vectors with new capsid serotypes for liver directed gene therapy in a large animal model, namely, the hemophilia A dog. This work builds upon our previous success in "curing" the hemophilia A mouse using FVIII gene delivery in two new AAV serotypes, AAV8 and AAV9. Our studies in hemophilia A dogs, while more modestly successful, have also been encouraging with both new AAV serotypes. In this application, we evaluate further these AAV serotypes, beginning with delivery of FVIII cDNA in heavy chain and light chain vectors. We test responses at two different doses for both AAV8 and AAV9, and compare intraportal to intravenous routes of vector administration, We then go on to develop an effective, smaller single chain vector that can be produced in high titers, and test this single chain vector using the best combination of serotype, dose, and route of administration. We will also carry out therapy with our best conditions in young dogs, in an effort to initiate treatment before the onset of serious morbidity and also to prevent inhibitor formation to rFVIII used for conventional therapy. Lastly, we will determine whether FVIII can be readministered to dogs using a different serotype vector from the vector used in the original virus infusion. In all of these studies significant efforts will be made to test the safety of the new AAV vectors, concentrating on studies of neutralizing antibodies, development of transaminitis, and germline transmission of virus. At the end of these studies, we expect to have discovered treatment conditions that consistently produce long-term therapeutic levels of FVIII (>10% of normal) in a large animal, the hemophilia A dog. These results should make clinical trials with AAV vectors an appropriate next step. [unreadable] [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
The aim of this project is to identify and characterize the gene or genes responsible for the Alagille syndrome. Elucidation of the genetic basis of the syndrome will necessarily include gene identification followed by studies of gene regulation, products(s) and function(s). It is likely that an understanding of the molecular events that give rise to the hepatic abnormalities in Alagille syndrome will also provide new insight into other hepatic and biliary disorders. The Alagille syndrome, which has a complex phenotype and inheritance pattern, has been localized to a small region of chromosome 20. The Alagille Syndrome is a clinically defined disorder characterized by cholestatic liver disease, a peculiar facies, structural heart defects, vertebral anomalies and ocular abnormalities. The association between Alagille syndrome and chromosome 20p was first noted in a case report describing a patient with del(20)p11.23-pter and a phenotype consistent with the Alagille syndrome. Despite the identification of the Alagille region, molecular characterization of the gene or genes causing the syndrome has not been achieved. In order to identify the causative gene(s), cytogenetic and molecular screening of large numbers of patients for deletions in the Alagille region will be performed. Once the region is more narrowly defined, candidate genes within the area will be selected for further study. Selection of genes will be accomplished by three methods. First, known markers will be mapped to chromosomal breakpoints and/or within deletions and those markers then will be used to select genomic and cDNA clones. Second, candidates will be selected from gene families with known functions that would be predicted to affect the organ systems with phenotypic abnormalities in the Alagille syndrome. Lastly, subtractive screening methodologies will be used to select sequences with altered expression in an affected liver sample. Once isolated, these candidate genes will be characterized by Northern blot analysis to determine the pattern of tissue expression in adult and fetal tissues. Southern blot analysis will be used to determine the incidence of hemizygosity, and single strand conformational polymorphism screening will be used to identify mutations.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Abstract: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) that eventually develops into chronic pancreatitis (CP). Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Importantly, HP patients have an extremely high risk of developing pancreatic cancer than other forms of CP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from the pancreas during the early stages of the disease and the lack of animal models that recapitulate the human form of the disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice at a level equivalent to that found in human HP. This new model will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies for its prevention and therapy. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors interact with genetic changes to increase trypsin activity, which causes pancreatitis by cell-autonomous cell death signaling pathways and non-cell-autonomous inflammatory pathways. We will characterize these signaling pathways in the HP model and investigate their roles by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the specific role of intracellular human trypsinogen activation during the pathogenesis of HP and provide new insights for preventive and therapeutic interventions. Importantly, our novel clinically relevant model will provide a powerful tool for developing and testing such interventions.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The long-term objective of this research is the development of a compact, robust, and user-friendly laser Source for 2-photon excitation in laser scanning microscopy. The use of 2-photon excitation in confocal microscopy offers a number of advantages for studies of cell physiology; however, the use of this technique is currently limited due to the specialized nature of the required sources of femtosecond duration pulses. 100- femtosecond pulses from a modelocked solid-state laser operating at wavelengths around 1.3 microns will be frequency-doubled to generate wavelength tunable ultrashort pulses in the desired wavelength range around 650 nanometers. A version of the modelocked laser which is pumped by an array of laser diodes will then be designed and built to reduce the size and enhance the stability and reliability of the source. There are no all-solid- state sources of 100-femtosecond pulses at the wavelengths which are needed, nor has there been a repone of a diode-pumped femtosecond laser at any wavelength. With a source having the required characteristics it will he possible to retrofit a large base of existing and future Scanning microscopes for 2-photon excitation.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Age-dependent changes in the circadian system of the mouse will be examined as a model of the same changes in man. The disintegration of the circadian rhythm of sleep-wakefulness in the age and exercise (wheel-running) restriction experiments documented in our previous grant will be studied in greater detail. The body temperature rhythm will be added to the existing automated EEG scoring system to enable assessment or the phase relationships among the sleep/wake, activity, and body temperature rhythms both during the aging process and during exercise restriction in young and aged mice. An additional activity measurement will be added to provide an index of activity during the exercise restriction experiments. We also intend to: 1) examine the temporal order among the sleep/wake, body temperature, activity and drinking rhythms in young and old animals as well as in exercise-restricted animals; 2) directly test the hypothesis that the age and exercise-restriction effects on the sleep/wake rhythm are mediated through the circadian system; 3) attempt to ameliorate the age-dependent decay in the sleep/wake rhythm by restricting wheel availability to a specific time of day; 4) evaluate whether the young mouse exhibits a circadian phase-dependent sensitivity to exercise restriction; 5) examine whether the deterioration of the sleep/wake rhythm in the aged animal is accompanied by a decrement in the benzodiazepine receptor rhythm; 6) measure local cerebral glucose metabolism using the [14C] 2-deoxyglucose technique in young and aged mice to attempt to identify the neural basis of the age-dependent decay or circadian organization, with particular attention to the metabolic activity of the suprachiasmatic nucleus (SCN); and 7) attempt to consolidate the sleep/wake rhythm in an animal whose circadian system has been experimentally disrupted by lesion of the SCN. We anticipate that these experiments will elucidate mechanisms underlying the age-dependent decay of circadian organization in the mouse and that these principles should be generalizable to sleep disturbances observed in aged humans.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objective of this project is to deliver a fully integrated CLIA-certified technology that provides diagnostic characterization of individually identified CTCs harvested from human specimens. We will use a novel patented chip-based dielectrophoretic-controlled isolation process (DEPArray) to identify and isolate single CTCs while maintaining their functional biological integrity. Using this technology we have developed a strategy for classifying CTCs into defined subsets with identifiable characteristics useful for clinical research and diagnosis. The specific tasks for this Phase I contract are to: 1) Establish a robust method for comprehensive detection and isolation of single circulating tumor cells 2) Define and isolate specific subsets of CTCs based on extracellular antigen expression 3) Demonstrate the ability to perform molecular analysis on single cells isolated from subgroups of CTCs 4) Demonstrate reproducibility of an integrated CTC Detection, Recovery, and Analysis system This SBIR contract will enable development of a fully-integrated and robust cell-identification and separation system to support CTC cancer research and diagnostics. This novel technology promises to revolutionize the identification of new subsets of CTCs and also assign clinically useful characteristics, such as metastatic potential, to each subset of cells.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Scientific information about human genetics is accumulating at an accelerating rate, but information about public knowledge, beliefs, and attitudes with respect to these developments is not. And yet such information is crucial for formulating prudent and humane social and ethical policies in these areas. The aim of this proposal is to add to the limited store of knowledge available about public values and attitudes relevant to various aspects of genetic technology. The proposal has two specific aims. The major aim is to investigate experimentally the determinants of people's beliefs about the relative contribution of heredity and environment to differences in such behavioral characteristics as aggression, shyness, and alcoholism. A second aim of the proposal is to investigate trends in knowledge about and attitudes toward genetic testing and genetic technology by replicating questions previously asked in two earlier studies. Given the rapid changes and developments in the field of genetics, and their increasing availability to the public via the mass media, we expect to see changes in attitudes as well. The vehicle for the study will be the 2004 General Social Survey (GSS), a national face-to-face survey of the adult household population of the U.S. The proposed study of beliefs about genetic and environmental influences on behavior will systematically vary (a) the social desirability of the condition or characteristic asked about as well as (b) the race/ethnicity and (c) the gender of the person manifesting the characteristic in order to determine how each of these affects the judgments made. In addition, we will assess the significance for such judgments of the rater's own sociodemographic characteristics (e.g. race, ethnicity, age, education, marital status, and religion), as well as such aspects of the rater's personality as locus of control, optimism-pessimism, and the need for self-esteem. By including four questions about genetic testing among those we add to the survey, we will be able to investigate beliefs about genetic and environmental influences on behavior. [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
The progressive immunodeficiency of HIV-1 disease is associated with multiple cytopenias, in particular loss of circulating CD4+ T cells. This protocol is designed to test the hypothesis that HIV-1 infection leads to peripheral lymphopenia by inducing a central defect in T cell production. If so, thymic mass and the number of recent thymic emigrants (CD3+CD45RA+CD27+ cells) in the peripheral blood should be expected to decrease as HIV-1 disease progresses. Changes in thymic mass is being assessed by non-invasive imaging by CT scan, using well-established techniques; changes in the phenotype of circulating T cells by multiparameter flow cytometric analysis of peripheral blood mononuclear cells. Volunteers within various age groups (20-29, 30-39, and 40-49 years old) with CD4 counts greater than or less than 500 are being chosen.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Affective science (the study of emotions, moods, affect-based pathology and other emotion-related phenomena) has expanded dramatically in recent years, having significant impact in psychology, psychiatry, neurology, and neuroscience. Our training program augments the specialized training predoctoral students receive in their chosen fields with substantive exposure to other traditions and methods within affective science. By sharing didactic, patient case conference, workshop, and other experiences over a three-year period, predoctoral trainees form a cohort group at an early stage of their career that fosters greater familiarity and comfort with clinical issues (mental illness, neuropathology) and stronger professional ties to those from other approaches and disciplines than would occur in traditional training. The multi-university nature of the training program greatly expands the community of affective scientists that trainees meet, learn from, and work with. The training program is built on the view that fostering an appreciation and understanding of the theories, methods, and data from areas beyond one's own area of specialization lays the groundwork for better communication among subspecialties, more interdisciplinary collaborations, and a stronger, more integrative and generative affective science. In this application for a third five years of support, we propose to continue selecting four new predoctoral trainees per year from psychology, neuroscience, and health sciences programs at four Bay Area universities (the Berkeley, Davis, and San Francisco campuses of the University of California and Stanford University). Trainees participate in a three- year training sequence leading up to their dissertation research that includes a year-long core training seminar, a bimonthly patient case conference, visits to training faculty laboratories at the four campuses, specialized workshops, and an annual conference where trainees' research findings are presented and discussed. Close mentoring and monitoring of trainee progress is maintained throughout. We believe that this method of training students has significant societal benefits, which derive from applying knowledge derived from basic affective science to a range of public health issues including: (a) mental health and illness; (b) physical health and disease; (c) attachment, loyalty, and relationship quality; (d) well-being; (e) addictions; (f) violence; (g) treatment design and evaluation; and (h) inter-group conflict and communication. [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
The need for new broad-spectrum antibiotics to combat multidrug resistant bacteria is a growing global problem that poses a legitimate threat to human health. Cationic antibacterial polymers represent a promising approach to address this problem due to their low cost, wide range of potential uses and a distinct mode of action that is much less prone to the development of resistance. A full development of this area, though, has been hindered by the current limitations in polymer chemistry. Whereas modern medicinal chemistry for small molecules has an arsenal of tools to precisely modify and optimize lead compounds, controlled polymerization methods are still reliant on a relatively small set of competent monomers. This proposal aims to systematically evaluate the structure activity relationships (SAR) of this class of antibiotics through the development of a novel strategy for the polymerization of sequence-programmed macrocycles. By combining a controlled polymerization method with a rapid ring closing/ring opening reaction, structural information built into the macrocycle will be translated to the polymer backbone to provide well-defined materials that have spatial control over long sequences and can incorporate chemical diversity. This strategy allows for the precise modulation of parameters that have been previously implicated in antibacterial activity: type and number of cationic groups, charge density, molecular weight and lipophilicity. The research will result in a better understanding of the structural features associated with antibacterial activity and will guide the design of next generation polymer therapeutics and coatings with improved potency and selectivity.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Asymmetric septal hypertrophy, or ASH, is a genetically determined myocardial disorder that is transmitted as an autosomal dominant trait. Disproportionate hypertrophy of the ventricular septum has also been observed and associated with certain congenital cardiac malformations. It is concluded that the results of this investigation indicate that while disproportionate ventricular septal thickening may occur in patients with a variety of congenital heart malformations, such a finding is not necessarily a manifestation of the disease spectrum of genetically determined ASH.
|
{
"pile_set_name": "NIH ExPorter"
}
|
This Laboratory has historically been involved in the study of tissue lesions mediated by the formation of chemically reactive metabolites of drug and other foreign compounds. A method has been developed to estimate in vivo the intrinsic clearances of enzymes that catalyze the formation of short-lived reactive metabolite. The basis for this method is that at low doses of the parent compound, the reactive metabolite preferentially reacts with endogenous substances such as glutathione (GSH). The depletion of GSH can be served as an index for the formation of the reactive metabolite. The assumptions made in this method are 1) the concentration of hepatic reactive metabolite reaches a steady state almost instantaneously, 2) the rate of the formation of reactive metabolite follows first order kinetics, and 3) the rate of the formation of the GSH conjugate follows second order kinetics. The animal model for this study was male hamsters. A marginally toxic dose of acetaminophen was used. The intrinsic clearance for the formation on chemically reactive metabolite was estimated from the rate of synthesis of hepatic GSH (calculated), the fraction of the dose of acetaminophen converted to GSH conjugate and reported values of hepatic blood flow. This intrinsic clearance for reactive metabolite formation was errified by measuring the rates of formation of the GSH conjugate in the 9000 x g supernatant fraction of hamster liver.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Seven monoclonal antibodies (MABs) against rat neurophysin have been produced and fully characterized. These MABS have been used in developmental studies in studies on the fetal rat hypothalamus. Differential expression of the specific properties of vasopressin- and oxytocin-neurons during development has been found. In addition, these MABs have been used to characterize the arginine vasotocin and mesotocin neurons in the Xenopus hypothalamus, where greater than 4000 neurons, which were found to contain these peptides, have been detected. Polyclonal antibodies have been generated against the various processing intermediates of vasopressin and oxytocin, as well as LHRH, and these are currently being used in RIA and immunocytochemical studies of the adult developing hypothalamus. Immunocytochemical studies have shown that vasopressin is coexistent with dynorphin in secretory vesicles in the neurohypophysis, and with CRF in the median eminence. The irregular (spinous dendrites) LHRH cells which develop during puberty, undergo this transformation independently of gonadal steroids. Ligand potency analyses of AVT (V2) receptors in the Xenopus A6 cell line and the toad bladder have shown that these amphibiansystems contain a novel V-2 receptor. A large repertoire of MABs have been produced against neuronal cytoskeletal proteins in the squid axon and the Xenopus nervous system. Analysis of the protein kinase-calcium activated protease-neurofilament complex in the squid giant axon has shown that the protein kinase is similar to type II casein kinase, but with a preference for histone substrates.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. A cardinal feature of ALI is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption. Strategies designed to attenuate vascular permeability could provide attractive novel therapeutic targets and approaches. We previously identified the protective effects of simvastatin, an HMG CoA-reductase inhibitor, in a murine model of ALI and defined potent anti-inflammatory effects of statins including augmentation of endothelial cell (EC) barrier function. Genomic studies of simvastatin-mediated EC gene expression identified the dramatic upregulation of integrin [unreadable]4, a laminin receptor expressed in numerous cell types including EC, suggesting a potentially novel ALI target. While information is limited as to the role of integrin [unreadable]4 in EC, integrins are known to serve as mediators of inflammatory signaling and we have recently confirmed the attenuation of lung inflammation associated with the inhibition of integrin [unreadable]4 in separate models of murine ALI and ventilator-induced lung injury (VILI). Accordingly, we now hypothesize that integrin [unreadable]4 mediates EC inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting. PUBLIC HEALTH RELEVANCE: Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. Although treatment options for ALI are severely limited we previously identified the protective effects of simvastatin, a drug commonly used to lower serum cholesterol levels, in an animal model of ALI and our subsequent genomic studies identified the dramatic increase in the protein integrin [unreadable]4 in response to simvastatin treatment. Accordingly, we now hypothesize that integrin [unreadable]4 mediates vascular inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Proteins are tenaciously bound to messenger ribonucleic acid (mRNA) in the cytoplasm of mammalian cells forming messenger ribonucleoprotein (mRNP) complexes. These mRNP particles occur unattached to ribosomes in cytoplasmic pools and engaged in translation in polyribosomes. Polysomal mRNP can be released as free particles by treatment with physical or chemical disruptive agents or as a consequence of translational level inhibition of protein synthesis. Murine sarcoma 180 (S-180) tumor cells reversibly accumulate cytoplasmic pools of inactive mRNP when protein synthesis is repressed at an initiation step by amino acid deprivation. The objective of the proposed study is to identify and characterize the protein components of S-180 mRNP and determine their possible role in translation level control of protein synthesis. Oligo(dT)-cellulose affinity chromatography and CsSO4 equilibrium density gradient centrifugation will primarily be used to isolate and characterize S-180 mRNP particles. Specific experimentation is designed to 1) identify and compare, by SDS-polyacrylamide gel electrophoresis, proteins associated with mRNA from S-180 cells actively engaged in protein synthesis and those which are repressed in translation by amino acid deprivation, high temperature shock, and arrest in mitosis; 2) classify mRNP proteins according to their association with the non-poly(A) or the poly(A) region of S-180 mRNA by specific ribonuclease elution of proteins from mRNP immobilized on poly(U)-sepharose columns, and 3) determine the arrangements of proteins on S-180 mRNA by limited fragmentation of mRNP.
|
{
"pile_set_name": "NIH ExPorter"
}
|
This is an application for a cooperative agreement (U54), "Mechanisms of Alcoholic Pathology" (MAP), between faculties of the Biomedical/Biotechnology Research Institute (BBRI) at North Carolina Central University (NCCU), a Minority-Serving Institution, and the Bowles Center for Alcohol Studies at The University of North Carolina (UNC) School of Medicine. This proposal represents a true collaborative effort between the NCCU and UNC faculty with both groups contributing significant effort and being essential to the success of this CMARCD Program. Within this proposal, an NCCU Administrative component and three Research Components will integrate with the UNC-ARC Administrative, Education, 5 Research Components, and Cores, as well as other activities at the Bowles Center for Alcohol Studies. The UNC-ARC investigates mechanisms of alcohol pathology across the spectrum of behavioral, tissue, and cellular pathologies that occur with alcohol exposure. This proposal will focus on cellular pathologies that easily integrate into the ongoing overall theme of the UNC-ARC. Thus, both the UNC-ARC research components and this U54 proposal are integrated around the central theme that alcohol-induced pathology involves molecular and cellular changes that occur with alcohol abuse and alcoholism. The objectives of this U54 partnership are: 1) To investigate molecular mechanisms of alcohol-induced cellular pathology. By conducting an integrated and focused investigation into the molecular mechanisms of alcohol pathology this proposal will make important contributions to understanding alcohol morbidity and will create an active and successful research program on alcohol pathology at NCCU;2) To provide scholarly education on Alcohol Pathology. The educational efforts in this proposal will educate NCCU students on alcohol pharmacology and alcohol related pathologies and health disparities through a combined Annual Alcohol Research Day, new alcohol course curricula developed by NCCU faculty, an alcohol seminar series hosted by the BBRI, the UNC Bowles Center for Alcohol Studies seminar series, and NCCU fellowships to students on alcohol pathology and minorities. Ultimately, this proposal will conduct, promote, support, and mentor research into mechanisms of alcohol pathology, creating an acfive and successful alcohol research program within the NCCU-BBRI that synergizes with the UNC-ARC to advance education and discoveries.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The endocrine pancreas is both the substrate for fundamental questions in developmental biology as well as the target of the disease diabetes mellitus, which affects millions of individuals worldwide. A detailed genetic and molecular understanding of pancreatic endocrine development will be essential if we are to manipulate islet cell fate and numbers in vivo. Our emerging understanding of pancreatic development is one in which, through interactions with surrounding mesenchyme, the initially unpatterned pancreatic epithelium is successively sub-divided into exocrine and endocrine compartments which subsequently differentiate, the latter containing the |3eta cells that produce insulin. Among the factors that dictate islet cell specification are many genes whose identities are now known. In fact, it is now possible to order these genes into a first order genetic regulatory network in terms of order of gene action, expression and functional interdependencies, and hierarchical relationships. This grant therefore poses the question: Do we already know enough, and can we sufficiently augment that knowledge, to begin to use this information to systematically engineer islets and islet cells in vitro? To accomplish this ambitious goal, we will undertake three Specific Aims that are highly integrated with multiple components of SysCODE. In Aim 1, we will generate complete gene lists for key early states in the developing endocrine pancreas. An initial effort in this area has already been accomplished (Gu et al., Development 131, 165-79, 2004). We will now augment this information with data from additional developmental stages, selected mutant states and first-generation proteomic analyses. In Aim 2, in conjunction with the SysCODE Computational Team, we will develop methodology to order these genes and selected proteins into a definitive gene regulatory network (CRN) in a format that is useful to both biologists and tissue engineers. Lastly, in Aim 3 we will collaborate with the SysCODE Tissue Engineering Team to implement a stem cell based, engineered model of pancreatic islet development and we will use the GRNs generated in Aim 2 to optimize pancreatic endocrine fate specification. In the out years of the grant, we will transplant the engineered islets into diabetic mice and assess their physiological function. Collectively, these efforts, in conjunction with the rest of SysCODE, will establish a transforming paradigm for regenerative medicine.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Program Summary This program will be used to prepare new investigators (at the rank of Assistance Professor or equivalent) or established investigators (at the rank of Associate Professor or higher) for careers in translational research. It is not a training program for graduate students, postdoctoral fellows, or clinical fellows. The career development program will provide guidance, advise, evaluation, and financial support for up to two faculty level persons per year. The goal is to allow motivated individuals to develop an independent research career in translational science focused on lung cancer.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Level of nicotine dependence is widely regarded as an important predictor of smoking cessation outcome, yet a nicotine dependence measure with proven validity and clinical utility has not been available. Results from a pilot study strongly indicated the potential value of an initial core of items (based on psychoactive substance abuse criteria applied to nicotine) as a means for improving understanding and measuring the nicotine dependence construct. The treatment and theoretical benefits of such an instrument prompt us to advance our pilot work towards a multidimensional measure of nicotine dependence with demonstrated validity and reliability that will also be easy to administer by both the self-report and the interview method. The proposed study will be conducted in two phases. In phase one, item construction and refinement. our aims are: 1) to write multiple sets of multiple items to operationally define several hypothetical constructs comprising the nicotine dependence syndrome and 2) to construct an interview/self-rating protocol. i.e. the Nicotine Dependence Scale (NDS). in phase two, a field test of the NDS, our aims are: 1) to use exploratory factor analysis to identify the underlying constructs amongst a total set of approximately 80 items. 2) to determine through confirmatory analysis the invariance of the identified factor structure across demographic and psychological subgroups, 3) to determine internal consistency and re-test reliability, 4) to estimate the ability of the total NDS score and the battery of factor scored variables, singly and in weighted linear combination, to predict smoking cessation outcome, 5) to estimate the association of the total NDS score and the underlying factor scores with such variables as number of cigarettes smoked daily number of past attempts to stop smoking, carbon monoxide level, and the Fagerstrom Test score. Subjects will be smoking cessation program participants from the American Cancer Society in New Yore City (n=600) and from the Veterans Administration Hospital in Loma Linda, California (n=200). Approximately 60% of ACS subjects and 5% of VA subjects will be females; about 15-20% in both sites will be nonwhite. The high cost of chronic tobacco use (it is the leading cause of death among US adults) warrants efforts aimed at improving cessation techniques. Increased understanding of and ability to measure the nicotine dependence construct is an essential part of that task.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Biliary atresia (BA) is a disease of infants in which the bile ducts are progressively destroyed (reviewed in (7)). If untreated, the disease uniformly progresses to biliary cirrhosis, liver failure, and death within 2 years. The initial treatment for biliary atresia is the hepato-portoenterostomy procedure, in which the biliary remnants are excised and a Roux-en-Y limb of jejunum is placed in contiguity with the exposed liver surface at the porta hepatis. This is successful in ~50% of cases (8-11), but even patients with apparently adequate biliary drainage may experience ongoing hepatic fibrosis and bile duct loss. Ultimately the majority of patients with biliary atresia will require liver transplantation. s a result, biliary atresia is the most common indication for pediatric liver transplantation in the US The diagnosis is often delayed due to a failure to distinguish the disease from physiologic neonatal jaundice. Conversely, the diagnostic work-up of the jaundiced infant is extensive, including blood tests, ultrasonography, nuclear medicine scans, liver biopsy, and intra-operative cholangiogram. The implementation of a sensitive non-invasive test for BA could accelerate the diagnosis, while also sparing children without BA unnecessary and invasive testing. Circulating microRNA is a novel category of biomarker that has never been explored in BA. The preliminary data presented in this proposal demonstrate that circulating microRNAs are specifically elevated in infants with BA in comparison to children with jaundice from other causes. Aim 1 of this proposal therefore aims to validate the use of microRNAs as non-invasive biomarkers for the diagnosis of BA. Another challenge in the care of children with BA is the prediction of outcome after hepato- portoenterostomy. If children can be identified prior to the development of these outcomes, more aggressive monitoring, nutrition, anticipatory counseling - and perhaps in the future, therapy - can be provided. Aim 2 of the proposal therefore focuses on testing the ability of circulating miRNA to predict survival with the native liver after hepato-portoenterostomy. The successful implementation of miRNA-based, non-invasive diagnostic and prognostic tests for BA promises to have an immediate and significant impact on children with the disease. It may also lead to insights regarding BA pathogenesis and progress, as well as applications in other liver diseases. PUBLIC HEALTH RELEVANCE: Biliary atresia (BA) is a disease of infants in which the bile ducts linking the liver to the intestine are destroyed. It is the most common reason for a child to need a liver transplant in the US. The goal of this proposal is to develop new non-invasive diagnostic and prognostic tests for BA, so that children can be diagnosed and receive treatment as early as possible, because this has a major effect on whether or not liver transplant will be necessary.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Very little is known about the mechanisms by which pathogenic mycobacteria infect the host. In addition, there is almost no information in the literature on how the bacterium regulates gene expression in the host environment. Bacterial pathogens, which maintain long-term residence within the host cells, also need a variety of strategies to help them adapt to harsh environmental conditions. Among them is the response to stress conditions, suggesting that intracellular pathogens experience a considerable amount of protein misfolding and damage within host cells. Similarly, the regulation of mycobacterial genes and coded proteins upon interaction with the host mucosa, and within macrophages are not well known. Lon protease has been shown to participate in the regulation of stress responses in Escherichia coli. In addition to the function as scavenger of damaged proteins, Lon performs important regulatory functions by degrading cellular proteins that control gene expression. The Lon protease has also been shown to be important for Brucella abortus survival in the host. More recently, Lon has been demonstrated to regulate the expression of Salmonella invasion-related genes by proteolysis of factors required for hilA (a major regulator of the pathogenicity island 1, SP11) expression. Inactivation of Ion in Salmonella typnimurium leads to a significant increase in the ability to invade intestinal -407 epithelial cells in vitro. Inactivation of Salmonella Ion was also associated with attenuation of the bacterium in human macrophages and mice. Mycobacterium avium and M. tuberculosis interact with the host mucosa (s) at the initial stages of the infection. Upon entry into the airways and intestinal tract, gene regulation needs to occur in a rapid fashion. While a number of required genes appear to be up-regulated by conditions existing in the extra-host environment, many other genes are not. Our hypothesis is that the regulation of many mycobacterial virulence genes may likely be influenced by the action of energy dependent regulatory proteases such as Lon, i.e. using protease-mediated post-translational regulation to rapidly adapt to different conditions. Recent work using subtraction hybridization, suggests that Lon is a protein required for the efficient interaction between M. avium and the intestinal mucosa . The Ion gene is present in both M. avium and M. tuberculosis genome sequence. We, therefore, propose to gain new insight in the post-translational regulation in mycobacteria by: 1- Determining whether the overproduction and/or inactivation of Ion in M. avium (as a model organism) impacts the ability to replicate in macrophages and invade mucosal epithelial cells. This work has the potential to unveil mechanisms used by mycobacteria to regulate virulence genes in the environment of the host. In case we confirm our hypothesis, future work will address the role of Ion in M. tuberculosis [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
Project III, proposes studies to determine the effectiveness and safety of new therapies for treating CF lung disease, and to define when they should be administered. In an initial series of studies, key cell biologic issues relevant to therapy of CF lung disease will be studied. These studies include the following: 1) identification of the cell type(s) within proximal and distal airway epithelia that express the cystic fibrosis transmembrane regulator (CFTR); 2) quantitation of the rates and types of cells that proliferate in proximal and distal airway epithelia of normal and CF lungs; and 3) evaluation of the consequences of over-expression of CFTR on functions of proliferative and differentiated airway epithelia cells. Major efforts will be devoted towards evaluating therapies in a newly developed mouse model of cystic fibrosis. This model was developed by homologous recombinant techniques that disrupted exon 10 of the CFTR gene, and is termed the CFTR(-/-) mouse. A common strategy will characterize all therapeutic trials. Because the mouse has sub-mucosal glands in the nasal but not lower respiratory tract, the effects of treatment modalities in the two regions will be compared. Each therapy will be tested in protocols designed to measure whether the therapy is protective against the development of bacterial lung disease, and in protocols designed to measure the effectiveness of the therapy in CFTR(-/-) mice with established bacterial lung disease. In a first series of experiments, pharmacologic therapies directed at modulating the Na+ and C1- ion transport properties of the CFTR(-/-) mouse airway epithelia will be studied. Aerosolized amiloride, a Na+ channel blocker, and aerosolized UTP, a triphosphate nucleotide, will be studied singly and in combination. In parallel, a series of gene therapy studies will be initiated. In one series of studies transient expression vector systems for treating CF lung disease will be tested. The initial agent for these studies will be the adenoviral gene transfer vector. In another series of experiments, integrative gene transfer vectors will be employed. The recombinant retrovirus will be the first of this type of vector studied. The efficacy of therapies will be quantitated by pulmonary function measurements (respiratory rate, timing indices, 02 saturation), respiratory microbiology, and respiratory tract histology. Safety indices, both general and drug/vector specific, will be studied. The long range goal is to characterize the relative safety and efficacy of various therapies, alone or in combination, and develop strategies to intervene safely and effectively at all stages of CF lung disease.
|
{
"pile_set_name": "NIH ExPorter"
}
|
This research involves amino acid sequence analysis of serum albumin from several species, including human, baboon, bovine, ovine, porcine, equine, and chicken. Three dimensional molecular models of serum albumin are being developed from data on amino acid sequence, disulfide bridges, helix content, and chemical modification. The purpose of this research is to relate the structure of serum albumin to its function and evolution.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Positron Emission Tomography (PET) is a rapidly emerging non-invasive imaging technique with the exceptional ability to provide quantitative functional information. Unfortunately, this modality is currently limited to a single approved radiopharmaceutical agent, 18F-FDG, which measures tumor metabolism. The potential of PET in oncology can be advanced substantially by development of PET tracers that can assess other useful clinical parameters, such as the quantitative measurement of tumor perfusion and hypoxia. Such information is extremely useful for diagnosis and staging of cancer. We propose to develop a micro 62Znfl2Cu generator to produce the 9.7 minute 62Cu PET tracer at very high isotonic concentration and further to develop kit formulations to provide instant synthesis of 62 Cu-bis(thiosemicarbazone) compounds. Phase I will concentrate on demonstrating the feasibility of the combined microgenerator and instant kits for the two perfusion tracers approximately Cu-PTSM and x2CU-ETS, and the hypoxia tracer 62 Cu-ATSM. In Phase II, the microgenerator and kit formulations will be fully developed for human use, INDs will be submitted to the FDA for the three compounds, and finally, limited clinical feasibility studies focusing on serial perfusion and hypoxia imaging completed in a brief imaging session will be performed. The resulting perfusion normalized hypoxia map is expected to produce a highly superior measure of regional tumor hypoxia and thus superior information to guide treatment. The distributable generator produced tracers, together with the widely expanding availability of PET, can have far-reaching benefits in cancer patient treatment and management.
|
{
"pile_set_name": "NIH ExPorter"
}
|
At the present time there is no specific treatment for human acute pancreatitis. Exogenously administered secretin given concomitantly with ceruletide (an acute pancreatitis inducing agent) has been shown to exert a striking protective effect on induction of the pathological process. The goal of this project is to evaluate the efficacy and safety of intravenously administered secretin in amelioration of established ceruletide induced acute pancreatitis in rats and dogs in an effort to provide a specific form of treatment for human acute pancreatitis. Specific aims in this study are first to establish the efficacy, safety and the optimal dose of intravenous secretin to ameliorate acute ceruletide induced pancreatitis in unconscious, pancreatic duct cannulated rats and also to determine whether this hormone can consistently reestablish normal pancreatic juice flow and protein output. Subsequently in conscious rat and dog models using prior, optimally established doses of secretin we will evaluate the ameliorative effect of this hormone on established ceruletide induced acute pancreatitis. Serum levels of lipase, amylase and trypsinogen and macroscopic, microscopic and ultrastructural changes in the pancreas will be used as markers for establishing the efficacy of the ameliorative process. This program is clearly directed toward development of a possible mode of therapy for acute pancreatitis in two animal species. Should our hypothesis that secretin therapy may ameliorate induced acute pancreatitis be proven, then extension of this work to assessment of the role of this hormone in human acute pancreatitis would appear reasonable. Any form of therapy that might ameliorate the severity of this disease in humans would be a very welcome addition to our presently limited therapeutic armamentarium.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Disturbances in certain cognitive functions are among the most debilitating and persistent symptoms of schizophrenia, and convergent lives of evidence indicate that these symptoms reflect dysfunction of the dorsolateral prefrontal cortex (DLPFC). Postmortem investigations of schizophrenic subjects suggest that this dysfunction may be associated with abnormalities in 1) afferents from the mediodorsal thalamic nucleus (MDTN) which terminate in layers deep 3 and 4; 2) pyrimidal cells located in layer 3; and 3) the chandelier class of GABA interneurons which provide inhibitory input to the axon initial segment of the pyramidal cells. However, understanding the functional significance and potential pathophysiological relationships of these abnormalities requires an appreciation of the roles that each of these neural elements play in the normal functional architecture of the DLPFC. The studies funded during the current grant period focused on the intrinsic excitatory circuitry furnished by layer 3 pyramidal cells, using the macaque monkey DLPFC as a model of the human. We found that these neurons give rise to horizontal axon collaterals that reciprocally link clusters of layer 3 pyramidal cells, arrayed as a series of stripes. A given group of interconnected stripes appears to form a discrete module that may serve to form a discrete modules that may sere to recruit and/or coordinate the activity of spatially-segregated groups of pyramidal cells. Differences across the cortex in the features of these horizontal connections suggest that they contribute to the regional specialization of function. Consequently, we hypothesize that the connectivity within a DLPFC module plays a central in the mediation of cognitive processes, such as working memory, that are disturbed in subjects with schizophrenia. In the proposed studies of monkey DLPFC an integrated set of anatomical and in vitro electrophysiological techniques will be used to test hypotheses regarding 1) the relationships between DLPFC modules (as defined by horizontal, intrinsic connection) and the organization of afferent inputs from the MDTN; 2) the shaping of the functional properties of a given stripe by within-stripe interactions between pyramidal cells and certain classes of GABA interneurons, including chandelier cells; and 3) the extent to which the reciprocal, intrinsic connections between stripes form unique modules. The results of these studies will inform our understanding of the normal functional architecture of the primate DLPFC, and will guide the conduct and interpretation of studies of DLPFC circuitry in schizophrenia.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The most prevalent problem in cancer therapy is the re-growth and metastasis of malignant cells after standard treatment with surgery, radiation, and chemotherapy. Gene therapy approaches have suffered from the inadequate transduction efficiencies of replication-defective vectors that have been used thus far. Replication-competent vectors represent an emerging technology that shows considerable promise as a novel treatment option, particularly for locally advanced or recurrent cancer. In contrast to conventional replication-defective retrovirus vectors, gene transfer using replication-competent murine leukemia virus (MLV)-based retrovirus vectors has proven to be highly efficient, resulting in >98% transduction throughout entire tumors over a period of several weeks in breast cancer, prostate cancer, and glioma models, even with an initial inoculum of vector supematant as low as 10e(4-5) total infectious units, corresponding to MOIs as low as 0.001. While various other replicating oncolytic viruses are now in development as cancer therapeutics, the use of replication-competent retrovirus (RCR) vectors has rarely been contemplated due to the potential risks that might be associated with uncontrolled spread of virus. In fact, MLV-based RCR vectors exhibit a significant degree of inherent tumor-selectivity, as extratumoral spread was undetectable by sensitive PCR assays in all normal tissues tested, presumably due to the intrinsic inability of MLV to infect quiescent cells, and MLV exhibits additional advantageous characteristics including a simple genome and well-characterized life cycle, fidelity of transcriptional regulation, and efficient non-lyric transmission of suicide genes which are stably expressed until maximal intratumoral vector spread and optimal timing for pro-drug administration is reached. Using RCR vectors expressing the suicide gene cytosine deaminase, we have now demonstrated highly efficient killing of cancer cells both in culture and in tumor models in vivo. Treatment of intracranial gliomas with RCR vector-mediated suicide gene therapy resulted in 100% survival for >120 days, compared to 0% survival of control groups in < 40 days, and viral persistence was observed in all metastatic ectopic foci. We now propose that the efficient and stable conferral of viral neo-antigens to the tumor cells present an opportunity to further improve the long-term efficacy of this therapy by combining multiple approaches, including (1) seroimmunotherapy by follow-up administration of radioisotope-conjugated antibodies directed against viral proteins, and (2) active immunotherapy by peripheral sensitization with tumor vaccines expressing viral antigens, combined with intratumoral gene transfer of immunostimulatory cytokines. In this application, we have combined the expertise of multiple collaborators to directly test these approaches in syngeneic intracranial glioma models in vivo. [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
Abstract Lumbar intervertebral disc degeneration is a cascade of cellular, structural and mechanical changes that is strongly implicated as a cause of low back pain. The central nucleus pulposus (NP) is implicated in the initiation of this degenerative cascade, where decreasing proteoglycan content and an associated reduction in hydrostatic pressure impair the ability of the NP to effectively engage the surrounding annulus fibrosus and to evenly distribute and transfer compressive loads between the vertebrae. There is a critical need for therapies for disc degeneration that restore disc structure and mechanical function by directly addressing the underlying biological causes. A key challenge to developing effective biological treatments for disc degeneration is the need to recapitulate the structural complexity and specialized extracellular matrix of the component tissues, which comprise cells of multiple developmental lineages. Here we propose to address this challenge by directly applying developmental paradigms to establish an optimized biological disc regeneration strategy. Embryonic and postnatal disc formation is regulated by cells derived from the notochord. These cells secrete an array of growth factors that regulate cell migration, proliferation, differentiation and extracellular matrix deposition, and ultimately, directly give rise to the NP itself. There is therefore intense interest in identifying notochordal cell-secreted factors and applying them to develop improved therapeutic strategies for disc regeneration. The ideal stage to investigate the regenerative potential of notochordal cells is when they are most actively contributing to embryonic and early postnatal disc development. Therefore the overall objective of this proposal is to establish the regenerative potential of embryonic, notochord-derived nucleus pulposus progenitor cells (NDCs). Specifically, we will define the growth factor expression profile of NDCs at key stages of embryonic and postnatal disc development using whole transcriptome sequencing (RNA-Seq), and directly establish the regenerative potential of NDCs as a function of developmental stage using an in vivo mouse model of disc degeneration. The results of this work will provide a roadmap for optimizing cell and growth factor-based therapeutics for disc regeneration.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The proposed research is designed to elucidate the role of hepatic subcellular organelles in the assembly and secretion of lipoproteins. Our approach is to interfere with these normal physiological processes in order to elucidate the pathological effects of such derangements on cellular function and to perturb the subsequent metabolism of plasma lipoproteins. An analysis of the process of lipoprotein assembly and secretion using correlative biochemical, immunochemical and ultrastructural techniques can provide important information concerning the role of specific lipoproteins in hepatic lipid transport and the pathological effects on the cell when the normal secretion of these lipoproteins is deranged. The studies will, therefore, utilize experimental models to investigate: the role of subcellular organelles in hepatic lipoprotein biosynthesis; the importance of glycoprotein synthesis in the secretion of lipoproteins by the liver; the effect of experimental inhibition of the enzyme lecithin:cholesterol acyltransferase by which regulates plasma cholesterol esterification on the metabolism of cholesterol and lipoproteins. The long-term objective of all of these studies is not merely the definition of the normal physiological processes involved in lipid transport but to gain an understanding of the normal control mechanisms involved in lipoprotein production and the effects of modifying or modulating these controls in order to better appreciate human derangements in lipoprotein metabolism. This is of particular importance in understanding the pathogenesis of atherosclerotic disease and other diseases characterized by disturbances in lipid and lipoprotein metabolism and, therefore, may provide information leading to the development of rational forms of therapy. BIBLIOGRAPHIC REFERENCES: Sabesin, S.M., and Koff, R.S.: D-Galactosamine hepatotoxicity. IV. Further studies of the pathogenesis of fatty liver. Exp. Mol. Pathol., June, 1976 (In Press). Sabesin, S.M.: Effects of acetoxycycloheximide on the metabolism of hepatic triglycerides in the rat. Exp. Mol. Pathol. (In Press) 1976.
|
{
"pile_set_name": "NIH ExPorter"
}
|
HIV-1 Vpr is a nuclear, virion packaged accessory protein encoded by all lentiviruses. SIV/HIV-2 encodes in addition, Vpx which maintains close sequence similarity. The hallmark of Vpr is that it induces G2/M cell cycle arrest. A key to understanding the role of Vpr/Vpx in virus replication and pathogenesis is the identification of the cellular proteins with which they interact. Several groups, including ours, recently reported the identification of a cellular complex with which Vpr and perhaps Vpx interact and through which they may function. The complex is an E3 ubiquitin ligase that consists of DDB1/DCAF1/CUL4A/ROC1. This complex regulates genomic DNA replication and damaged DNA repair by mediating the destruction of cellular proteins including the DNA replication-licensing factor CDT1, STAT1 and STAT2 and other, yet to be identified substrates. The identification of the interaction with the E3 ubiquitin ligase presents a unified explanation of how Vpr may mediate its effects and provides a framework to elucidate the role that Vpr plays in HIV-1 pathogenesis. Other viruses encode proteins that target this complex, using it as a means to induce degradation of STAT proteins to inhibit type-I interferon responses. We will determine whether Vpr acts through its interaction with the complex to arrest cells in G2, induce apoptosis and activate DNA damage signaling pathways. In addition, cellular proteins that bind to Vpx and to DCAF1 will be identified and characterized. Thirdly, the project will test they hypothesis that Vpr/Vpx play a role in dampening innate immune responses to the virus. Innate immunity has over the past several years become a topic of great interest. The project will determine whether Vpr/Vpx may constitute another such mechanism. PUBLIC HEALTH RELEVANCE Cells have mechanism by which they resist infection by viruses. These mechanism are of great interest because they provide new avenues for the development of antiviral drugs. Viruses have evolved means of escaping these so called innate immune mechanisms. HIV, for example produces a protein called virion infectivity factor( VIF) that inactivates one of the antiviral proteins that are produced by blood cells. In this project we will study an HIV protein called viral protein R (VPR) that may serve as yet another means by which the virus avoids the innate immune mechanisms. When a cell is infected with HIV, Vpr is produced and as we recently discovered, binds to a cellular protein called damaged DNA binding protein 1 (DDB1) in association with another protein called DCAF1. DCAF1/DDB1 is a molecular machine of the cell that destroys unwanted proteins. Our findings have shown that Vpr causes DDB1 to degrade certain cellular proteins and we hypothesize that at least one of these is an antiviral protein that the virus needs to destroy in order to replicate. The project will identify the targets of DDB1 and understand how these proteins work against the virus. In addition, Vpr seems to affect the normal function of the DCAF1/DDB1 complex and thereby disrupt functions in the cell such as DNA repair and DNA replication. The project will determine how this happens and how it affects replication of HIV. [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
A multidisciplinary group of investigators with expertise in comparative medicine, pathology atherosclerosis, biochemistry, lipid metabolism, and neutrophil and platelet function will seek answers to pertinent questions about the effect of dietary fish oil on plama lipids, platelet and neutrophil lipid composition and function, and atherosclerosis in Cercopithecus acethiops (vervets). Animals with or without 1 clip 2 kidney hypertension will be fed diets with or without fish oil in a 2 x 2 factorial experiment. Platelet aggregation and platelet survival will be measured. The effect of incorporation of eicosapentaenoic acid into cell membranes on the products of cyclooxygenase and lipoxygenase pathways will be studied in platelets and neutrophils along with effects on production of prostacyclin by the artery. These effects will be compared to those of the products of arachidonic acid. The animals will be fed the experimental diets for 3 years. The long-term effects of fish oil either beneficial or adverse will be assessed, and the amount of atherosclerosis determined morphometrically. Short-term studies and epidemiologic studies suggest that fish oil should have a beneficial effect on cordiovascular disease. Our long-term objectives are to clarify the mechanisms of any beneficial or adverse effects and to determine the optimum level of dietary fish oil to obtain the greatest benefit with least adverse effect.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Aphasia strikes approximately one in 250 Americans. The reduced ability to communicate with language represents, in most cases, a catastrophic loss of self-sufficiency and a source of profound social isolation. No treatment for aphasia reported to date has reliably brought about changes in language production that migrate from highly constrained laboratory tasks such as single picture description to more challenging and socially functional tasks such as the production of entire narratives. The current climate in health care limits access to speech therapy, and thus it is imperative to develop approaches to treatment which allow patients to supplement 1:1 clinical treatment with intensive independent home practice. We have developed two computer programs to address the need for effective aphasia treatments that can be used semi-independently. One is a communication system (CS), which allows aphasic users to record spoken sentences a single word or phrase at a time, to replay these words or phrases, and to build them into sentences and narratives by manipulating visual icons on a computer screen. The other program is a language therapy system (TS) incorporating speech recognition and natural language understanding technology, which allows the computer to 'understand' the patient's spoken sentence and to provide feedback about whether it correctly describes a picture on the screen. This allows independent home practice of spoken language. The goals of this project are: (1) to replicate pilot results showing measurably more structured language production by aphasic patients using the CS, and to link these effects to characteristics of subjects' language processing impairments (Exp. 1); (2) to assess the impact of enhancing the CS with word-finding support for more severely impaired patients (Exp. 2); (3) to replicate the positive outcomes in pilot studies which used the TS and CS to improve aphasic patients' spoken language production, and to use the TS to train subjects on grammatical structures that provide tests of specific hypotheses about the impact of impaired short term memory on aphasic production (Exp. 3); and (4) to use data automatically collected by the CS to investigate the nature of the underlying disruption and to motivate the most effective approaches to remediation (Exp. 4). Information obtained from these studies will provide a basis for the further development of novel, theoretically motivated approaches to aphasia treatment.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Colorectal cancer is the second most commonly diagnosed cancer found in men and women in the United States. The vast majority of mortality of colorectal cancer patients is associated with formation of liver metastasis. According to American Cancer Society, the 5-year survival rate of colorectal cancer patients is 92% if the cancers have not metastasized. However, the 5-year survival rate drops to 7% once the cancer has metastasized to the liver. There is no effective therapy for metastatic colorectal cancer and prospects for cure remains poor. Resistance to apoptosis is a hallmark of metastatic human colorectal cancer. In humans, Fas is constitutively expressed in normal colon tissues, However, Fas expression is diminished in colorectal carcinoma, and complete loss of Fas expression and function is frequently observed in metastatic colorectal cancers. Induction of tumor cell apoptosis is the basis of many cancer therapies, including colorectal cancer therapies. Therefore, acquisition of resistance to apoptosis is one of the most significant challenges in colorectal cancer therapy. We have identified Interferon Regulatory Factor 8 (IRF8) as an essential regulator of apoptosis in human colorectal cancer cells. Furthermore, we observed that IRF8 expression is silenced in the vast majority of metastatic human colorectal cancer specimens through the IRF8 promoter DNA hypermethylation. In addition, ectopic expression of IRF8 restored the sensitivity of metastatic human colon carcinoma cells to Fas-mediated apoptosis in vitro and inhibited the growth of primary human colon carcinoma in a xenograft mouse model in vivo. Based on these novel observations, we hypothesize that IRF8 is a spontaneous colorectal cancer metastasis suppressor that functions through regulating tumor cell sensitivity to apoptosis, and metastatic colorectal cancer cells use the IRF8 promoter hypermethylation to silence IRF8 expression to acquire a metastatic phenotype. To test our hypothesis, we will pursue the following two specific aims: 1) to elucidate the molecular mechanisms underlying epigenetic regulation of IRF8 expression in human colon carcinoma cells;and 2) to determine the roles of IRF8 in spontaneous colon carcinoma metastasis in vivo, and to explore the potential of IRF8 mechanism-based therapies in suppression of colorectal carcinoma metastasis. Successful completion of this proposed research project will not only validate our hypothesis that IRF8 is a novel spontaneous metastasis suppressor but will also provide the molecular basis for the development of IRF8 mechanism-based therapies to target the deadly metastatic human colorectal cancer. PUBLIC HEALTH RELEVANCE: This proposed research project will elucidate the molecular mechanisms underlying epigenetic regulation of IRF8 expression in metastatic human colon cancer, and explore the potential of targeting IRF8 expression in combination with TRAIL therapy for the intervention of human colon carcinoma metastasis in vivo. Successful completion of the proposed research will provide a novel strategy for targeting the deadly metastatic human colorectal cancer.
|
{
"pile_set_name": "NIH ExPorter"
}
|
This is a multicenter, double-blind placebo controlled trial to assess the effectiveness of DHEA (dehydroepiandrosterone) in female patients with active systemic lupus erythematosus. The primary objective of this study will be to demonstrate improvement in the disease and/or its symptoms and to assess the safety and tolerability of 200 mg/day of DHEA.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Sunlight, ultraviolet (UV), exposure to the skin triggers cutaneous and systemic lupus (SLE) through an unknown mechanism. MRL (1Faslpr mutation) mice share features with human discoid lupus (DLE) and SLE (most notably lupus nephritis), and thus are valuable for understanding the pathogenesis of DLE, and its relationship to kidney disease. Colony Stimulating Factor 1 (CSF-1), the major macrophage (MX) growth factor, is pivotal in lupus nephritis in MRL-Faslpr mice. Our data suggest that CSF-1 is central to DLE in MRL-Faslpr mice. Enhancing systemic CSF-1 using CSF-1 transgenic MRL-Faslpr mice elevates circulating "inflammatory", activated monocyte (Mo), leading to an increase in MX in the skin and hastening the onset of DLE. Moreover, increasing cutaneous CSF-1 via implanting CSF-1 producing cells in the skin or UVB-exposure, triggers MX and apoptotic cell rich DLE in lupus-susceptible, MRL(1Faslpr), but not lupus-resistant mice. Conversely, CSF-1 deficient MRL-Faslpr mice exposed to UVB are resistant to DLE. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to the recruitment and activation of MX that, in turn, release mediators, which induce apoptosis in keratinocytes. Moreover, human translational findings indicate that CSF-1 is elevated in the serum/urine of lupus patients with DLE compared to healthy individuals. We propose to test the hypothesis that UVB-incited CSF-1 expression in the skin initiates MX mediated DLE. And in such hosts, UVB-incited circulating CSF-1 leads to DLE along with SLE. To test this hypothesis, we constructed novel, mutant MRL-Faslpr mice expressing distinct levels of CSF-1 (high, intermediate, none), individual CSF-1 isoforms, and reporter genes for identifying cells expressing CSF-1 and CSF-1 receptors (R) in tissues. The Specific Aims are: 1) To test the hypothesis that blocking CSF-1 is a therapeutic, and CSF-1 in the skin and/or serum is required for UVB triggered DLE in MRL-Faslpr mice. We will determine whether blocking the CSF-1R suppresses UVB-incited DLE, and explore the role of CSF-1 in the circulation and skin in mediating photosensitive DLE. 2) To test the hypothesis that aberrant MX responsiveness to CSF-1, and MX interactions with other immune cells, are required for UVB-incited DLE in MRL(1Faslpr) mice. We will determine whether MX are required/sufficient for UVB incited CSF-1 dependent DLE using genetic strategies, and determine whether aberrant MX responsiveness to CSF-1, leads to an influx of immune cells central to UVB-incited DLE. 3) To test the hypothesis that UVB triggers CSF-1 dependent, MX mediated SLE in MRL-Faslpr mice. We will determine whether UVB-incited CSF-1 triggers lupus nephritis, and determine whether circulating CSF-1 is the conduit between UVB-exposed skin and lupus nephritis. 4) To test the hypothesis that CSF-1 and MX are increased within skin lesions in patients with DLE and that CSF-1 generated in skin augments systemic (serum/urine) CSF-1 in DLE and SLE. Thus, these studies will provide insights into identifying new therapeutic targets for DLE/SLE by uncovering an essential piece of the sunlight/lupus puzzle. PUBLIC HEALTH RELEVANCE: Sunlight triggered skin and systemic disease is common in lupus, but poorly understood. We propose to pinpoint the role of Colony Stimulating Factor 1 (CSF-1) and CSF-1 receptor bearing cells (macrophage) in photosensitive lupus. By identifying an essential piece of the sunlight/lupus puzzle, these studies will provide insight into predicting the progression of lupus and identifying therapeutic targets to combat skin and systemic lupus.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Neonatal encephalopathy and associated brain injury is a serious problem that results in an estimated 1 million annual neonatal deaths despite major advances in obstetrics and neonatal care. Recent studies have shown that cooling babies who suffer neonatal brain injury to 33.5? C for 72 hours, a process known as Therapeutic Hypothermia (TH), can markedly reduce brain injury in about 50% of affected babies. However, it appears to be more effective in neonates who have a sentinel event at the time of birth and basal ganglia injury on MRI than in those with intervascular boundary zone (watershed) injury identified on MRI. Neither the exact mechanisms by which TH reduces brain injury nor the reasons that the treatment is effective in some babies but not others are understood. It is known that neonatal brain injuries have a mixture of characteristics and, probably different mechanisms. Therefore, different treatments might eventually be tailored to individual babies based upon the type of injury and response to initial therapy. This study proposes to use techniques involving magnetic resonance imaging, called diffusion tensor imaging (DTI) and proton MR spectroscopy (MRS) in the neonatal period to assess which types of injury respond best to TH. A later MRI study at age 6 months from this cohort will use more sophisticated methods to evaluate how severe the injury was and how well the body was able to repair the injury with the help of TH as compared to prior studies without TH. Finally, MRI scans will be obtained at ages of 8-10 years from patients that were enrolled in an earlier study. Children who had very similar injuries will be grouped together and the MRI results will be used to see what MRI characteristics (using the more sophisticated MRI methods) are found in the children who recovered best from their injury but not in those who did not recover well. These MRI characteristics will be designated as markers of brain repair after neonatal injury. Knowledge of these markers will help to more quickly evaluate new therapeutic interventions being used to increase repair after neonatal brain injury.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Studies will be carried out to gain a clearer understanding of Toxoplasma and toxoplasmosis. Since intracellular organisms are causing increasing morbidity and morality in immunosuppressed patients, the immunological aspects of Toxoplasma and toxoplasmosis are being studied to define the antigenic nature of the organism as well as the nature of the immune response and the relative importance of cells versus conventional circulating antibody in immunity against intracellular organisms per se. To gain a better understanding of congenital toxoplasmosis the mechanism of transmission from acutely and chronically infected mothers (both human and animal) as well as the role of maternal antibody in inhibiting an immune response in the infected fetus is being studied. The important area of infection in the immunologically compromised host is being studied using Toxoplasma as a tool to study resistance to intracellular infection. The largest single group of patients which we are studying at present are Hodgkin's disease and cardiac transplant recipients. The variability in resistance to infection among various population groups and the differences noted by sex led us to develop a model with Toxoplasma and inbred strains of mice. A major effort is being made to define the genetics of host resistance and susceptibility to Toxoplasma and the underlying mechanisms. BIBLIOGRAPHIC REFERENCES: Hyde, B., Barnett, E.V., and Remington, J.S.: Method for differentiation of non-specific from specific Toxoplasma IgM fluorescent antibodies in patients with rheumatoid factor. Proc. Soc. Exp. Biol. Med. 148:1184-1189, 1975. Remington, J. and Desmonts, G., in Remington, J. and Klein, J. (Eds): Infections of the fetus and newborn infant, Philadelphia; W.B. Saunders, 1976.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Ad lib fed 300-350 g Wistar rats were implanted with cannulae in the external carotid artery, the pancreato-duodenal and hepatic vein 5-7 days prior to oral administration of ethanol sufficient to elevate blood ethanol to 30-40 mM. We then determined the concentration of liver 3H20, 14C-insulin and 51Cr-red space, the concentration of 1-Alanine and 1- Glutamate -, NH4+ and inorganic electrolytes within the three vessels and within freeze-clamped liver as well as the potential (EN) between extra- and intracellular phases of liver. The calculated deltaG[Na=} between hepatic vein/liver increased from +11.2 to +14.5 kJ/mol. The deltaG[1- Glutamate-] gradient between hepatic vein/liver was about -13kJ/mol with or without ethanol suggesting that the reaction was close to near- equilibrium with the energy of sodium. The deltaG[1-Alanine] between hepatic vein/liver differed both in magnitude and direction of change after ethanol treatment from ~G[Na+] hepatic vein/liver; it was -4.23 kJ/mol in control animals and decreased to-2.6 kJ/mol after ethanol treatment. The result is compatible with a net 1-Alanine/NH4+ exchange rather than Na+ linked 1-Alanine co-transport. The sum of ~G[1-Glutamine] hepatic vein/liver + ~[NH4+] hepatic vein/liver was found to equal deltaG[Na+] hepatic vein/liver. Oral administration of ethanol inhibited uptake of arterial 1-Glutamine by intestine, decreased the hepatic ~G 1- Alanine portal vein/liver to 0, increased the deltaG1-Glutamine portal vein/liver and its co-transport partner deltaG[Na+] hepatic vein/liver with which it appeared to be in near-equilibrium according to the intrahepatic glutamine synthase (EC 6.3.1.2) reaction from 5.56x10-9 M, a value close to 1.20x10-9 M expected at near-equilibrium to a value of about 1x10-8 M.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The Neuromotor Function Core (RC-2) provides support for research conducted in University of Maryland,[unreadable] Baltimore (UMB) OAIC studies. The RC-2 enhances Pepper Center goals by providing the expertise and[unreadable] investigator resources to. assess the biomechanical and neurological mechanisms of functional performance[unreadable] with particular emphasis on gait, reaching and balance in older people with physical disabilities due to stroke,[unreadable] hip fracture or other chronic diseases associated with aging and disability. RC-2 aims are to:[unreadable] 1. Provide reliable functional and neurological measures to enhance the rehabilitation science in OAIC-supported[unreadable] clinical research studies which investigate the mechanisms underlying the physical and[unreadable] neuromuscular limitations of older individuals with stroke, hip fracture and other chronic diseases.[unreadable] 2. Develop new methodology to investigate deficits in neuromotor control and brain function in older disabled[unreadable] individuals and, in collaboration with RC-1, facilitate the implementation of motor learning principles and[unreadable] new technologies into novel exercise rehabilitation interventions that can be tested in the laboratory and[unreadable] then, if efficacious, be translated into the community.[unreadable] 3. Conduct research examining central and peripheral neural mechanisms in focused rehabilitation studies[unreadable] that are already shown to be efficacious to better understand the mechanisms of exercise-mediated[unreadable] neural adaptations underlying motor recovery and inform the design of new interventions.[unreadable] 4. Provide consultation, mechanistic insight and training to Junior Faculty and OIAC investigators, other[unreadable] Pepper Centers and investigators studying rehabilitation of older people with physical limitations at other[unreadable] institutions in the selection and use of functional and neuromotor assessment tools and assist in the[unreadable] interpretation of the research findings.[unreadable] Conduct of laboratory-based and standardized measures of functional performance, cortical and peripheral[unreadable] neuromuscular adaptations in the RC-2 allows strict maintenance of blinding as critical mechanistic outcomes[unreadable] are determined, and eliminates duplication of expensive testing equipment. Collection of functional,[unreadable] biomechanical and non-invasive neurophysiologic data by RC-2, and subsequent integration with data[unreadable] collected in other Cores enables a comprehensive, multi-disciplinary examination of mechanistic factors[unreadable] associated with novel rehabilitation intervention in stroke and hip fracture. Internal to the Pepper Center, RC-[unreadable] 2 is the primary support core for a CDP on proximal and distal arm training in stroke, a P/ES on bilateral[unreadable] robot-assisted ankle training in stroke and secondary support on a CDP for comparing impairments with[unreadable] muscle abnormalities, a P/ES on treadmill training in older individuals with HIV and a P/ES on treadmill[unreadable] training in hip fracture. The RC-2 is supports and is supported by 9 externally funded grants.[unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
Injuries associated with MMH continue to pose a significant problem to industry, both in terms of human suffering and economic losses. Three approaches to the control of such injuries have been employed: (1) ergonomic job design, (2) replacement screening, and (3) training and education. While ergonomic job design is effective, it has not alleviated injuries associated with MMH. Due to the effectiveness of training and education, replacement screening is the most promising method to augment ergonomic job design. The first specific aim of the proposed research is to empirically investigate the role that power, the dot product of force and velocity, may have in determining an individual's lifting capacity. Twenty five male subjects will participate in the experiment. Power will be assessed through both isokinetic and isoinertial techniques. It is hypothesized that power plays a greater role in lifting capacity that previously used measures, particularly isometric strength. The second specific aim of the proposed research is to elucidate the relative importance that strengths - measured by various techniques have in predicting lifting capacity. Isometric strength, power assessed rough isokinetic and isoinertial techniques, and isoinertial lifting capacity measured on the X-factor 6 ft, incremental lifting machine will be related to maximum lifting capacity through statistical methods. Thus, the secondary aim is more general than the first aim, but will provide a useful and informative comparison f several techniques used by previous researchers, as well as power which is proposed here. The proposed research can best be described as a pilot investigation that will provide valuable insight or future investigations which cover a broader set of task conditions and a larger subject pool. At this time, the relative contributions of various strengths to lifting capacity are unclear, and the proposed research will reduce this uncertainty. Once the most important determinants of lifting capacity are understood, a large- scale study can be designated which could result in the ability to predict lifting capacity with more precision ban current models provide. The proposed research will also provide insight into how dynamic capabilities, as opposed to static measures very popular in previous research, influence lifting capacity.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The objective of the Baylor Research Training Program for Pediatricians is to provide didactic structure and mentoring for post-doctoral M.D. fellows, who are committed to academic careers in pediatric subspecialties. The department has three highly focused T-32 training grants supporting only 13% of such postdoctoral fellows in the department. Our program's strength ties in the availability of the resources of one of the largest Departments of Pediatrics in the country', which include: 1) well established, peer review funded, pediatric investigators with a track record of mentoring; 2) excellent research resources, programs and facilities; and 3) a large number of fellowship programs that attract high quality young pediatricians. The proposed training plan will: 1) facilitate the development of their individual didactic and research training programs; 2) provide stipends to protect time for their individual research and educational efforts; 3) provide educational support in the area of study design, statistics, molecular biology, and/or other cognates; 4) assure an appropriate and successful Mentor match; and 5) make available the resources of the Department and Baylor College of Medicine to facilitate their cost effective research activities. The proposed program has 45 clinical and basic science investigators as mentors. All mentors have active research programs and vast majority of them have expertise in mentoring physician-scientists. Scholars will develop a 5-page research proposal with their mentors as part of their applications to the program. All applications will be reviewed by an Executive Advisory Committee selected from the overall mentoring faculty. The educational support is derived from the clinical and basic science curricula at Baylor, together with divisional and departmental seminar series. Over the last 10 yrs we have successfully used this approach to mentored research training for the academic development of pediatric faculty in the Children's Health Research Center grant, which has fostered the career development of 32 physician investigators, of which 80% remain in academic medicine, 21 of which are current members of the Baylor faculty. We believe this success reflects the departmental and institutional commitment to the training of young physician scientists. The funding of this program will help train academic pediatricians who will improve the health and care of the next generation of children in our country and throughout the world.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Jackson State University (JSU) is committed to increasing the number of Underrepresented Minority Students participating in the field of Biomedical Research. The historical mission of the university has been to foster an environment dedicated to student achievement in populations that have traditionally been underserved. JSU believes that in order for any student to achieve success in biomedical research careers, a student must learn foundational skills (reading, writing, speaking, listening, and numeracy), develop critical thinking skills, and master analytical inquiry (metacognition and ethical development). This proposal attempts to intentionally develop these skills through the RISE-S.T.E.P.S. program. This proposed program contains three program components; Curriculum Enrichment, Biomedical Research Enhancement, and Interpersonal Development and Social Integration. This proposal will combine best practices found within the university in other disciplines, current literature, and accepted mentoring approaches to increase the number of students that not only desire to become biomedical researcher, but have the tools to be leaders in their respective fields.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Our research plan follows the long range goals stated in the initial proposal. Specifically, we plan to: (1) Isolate the yeast histone genes on recombinant DNA plasmids. (2) Determine the organization of the yeast histone genes by renaturation kinetics, restriction mapping, and DNA sequencing. (3) Use the cloned histone genes to study control, both in the cell cycle and at the level of control sequences in the genes. (4) Use plasmids containing DNA galactose pathway to measure the timing of mRNA for each during the cell cycle. (5) Since it is now possible to fractionate poly(A) based on size (using the Sephadex LH 20-100/GLYME chromatography system) we will be able to follow the processing of poly(A) to determine if the (A)90 species is a precursor to the two smaller classes, as well as the dependence on protein synthesis for poly(A) shortening. (6) The presumed ribonucleoprotein particle can be further characterized as to (a) nature of the associated proteins; (b) translatability of the large RNA in vitro (in collaboration with Dr. J. Hopper); (c) possible processing of the RNA; and (d) fate of the particle in mutants (ts136) which fail to transport RNA at the restrictive temperature. This might allow one to dissociate processing in the nucleus from transport to the cytoplasm.
|
{
"pile_set_name": "NIH ExPorter"
}
|
The importance of skin pigmentation, particularly with respect to its implications for photoprotection against skin cancers (including malignant melanoma), has resulted in a dramatic surge in research on this topic. The alarming increase in incidence of skin cancers (especially melanoma) has been a major stimulus behind those efforts. Our laboratory continues to remain at the forefront of research on the regulation of mammalian pigmentation and focuses on characterizing: (1) pigment-related genes and their functions involved in melanocyte differentiation, (2) the biochemistry of melanins formed in the skin and their photoprotective properties, and (3) the biology of melanocyte specific differentiation antigens that serve as melanoma-specific targets. This research project is focused on characterizing parameters important to the growth, differentiation and function of normal melanocytes, and their significance to the growth and/or the metastasis of transformed melanocytes (malignant melanoma). These studies have evolved into an examination of the function and regulation of pigment-related genes, i.e. genes that encode melanocyte-specific proteins. Such proteins have generally been found to be localized in melanosomes, specific organelles that serve as the site of melanin pigment deposition; they function as catalytic and/or structural entities but perhaps more importantly, serve as specific targets of host immune responses to malignant melanoma. Our efforts in this regard have recently been targeted in 4 primary areas of interest, all of them dealing with structure, function and/or melanoma-targeting of melanosomal proteins.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Cytoplasmic guanylate cyclase, a heme-containing enzyme catalyses the conversion of guanosine 5'-trisphosphate to cyclic guanosine monophosphate which mediates numerous biochemical events including vascular smooth muscle relaxation, platelet deaggregation, photoreceptor cell signaling, ion transport in gastrointestinal cells, neurotransmission, relaxation of corpus cavernosum (impotence) and myeloid cell differentiation. The activity of soluble heme-containing guanylate cyclase is markedly increased by endothelium-derived relaxation factor (EDRF or nitric oxide) and several clinically employed nitric oxide generating vasodilators. Stroma free hemoglobin, considered by some as a possible blood substitute, binds nitric oxide strongly and thereby inhibits the activation of guanylate cyclase by nitric oxide. This proposal is directed towards the key area of understanding the mechanism of guanylate cyclase activation. The studies proposed here will define the role and the steric environment of heme and nitric oxide in guanylate cyclase activation by studying its reactions with various ligands in picosecond the second time domain. These studies will be made by single and double mixing stopped-flow spectrophotometry and ultrafast flash photolysis. The extensive data base for hemoglobins and other heme proteins will form the basis of interpreting the kinetic data for similar reactions of guanylate cyclase. The reactivity of the protein thiols in the activated and nonactivated forms the enzyme and their participation in the formation of nitrosothiol intermediates will also be investigated by kinetic methods. Studies on the reactivity of the heme-moiety and SH groups will be accompanied by the study of steady-state enzyme kinetics under identical conditions. We propose a model in which the dynamics of ligand binding with heme and its synergistic or antagonistic effect on heme binding with protein plays a crucial role in modulating the enzyme activity. We propose studies with heme-model compounds and heme-proteins to investigate the trigger mechanism in guanylate cyclase activation.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Skeletal muscle contractility is defined as the capability of the contractile proteins in a muscle to interact and generate force. All body movements are dependent on contractions of skeletal muscles. Consequently, any decline in skeletal muscle contractility results in some degree of immobility. Contractility is impaired by many muscle diseases, random and engineered genetic mutations, and even healthy aging. Quantitative knowledge of the contractility of skeletal muscles is necessary to test hypotheses regarding the interactions between deficits in basic cellular and molecular processes and musculoskeletal frailty and immobility. Briefly, the specific aims of the Core are to provide for NSC investigators: (1) facilities, expertise, and technical support for measuring contractility of whole skeletal muscles and small strips of intact fibers from the diaphragm muscle (2) instruction and training in the knowledge and skills necessary to measure contractility; and (3) development of techniques and/or construction of specialized apparatus for the study of the contractility. Contractility is measured initially at the level of the whole skeletal muscle to provide the broadest spectrum of functional changes arising from cellular and molecular changes in skeletal muscle fibers due to aging or experimental interventions. At later stages in a project, more sophisticated evaluations may be required at the cellular or molecular levels. The Contractility Core was developed to ensure that all NSC investigators are able to include valid and reliable measurements of skeletal muscle contractility in their experiments. Consequently, the Contractility Core provides free to any NSC investigator: (1) one study of six pairs of control and experimental rodents; (2) assistance in education and training NSC investigators, their staff, or trainees to set-up the apparatus and measure contractility independently; and (3) assistance in the development of one innovative technique, or the construction of one specialized instrument for the measurement of contractility per year. Subsequent use of the Core is generally on a fee-for-service basis, but if results are promising and particularly if the NSC investigator proposes to seek outside funding, additional experiments may be supported by the Core budget from unallocated charge-back-fees. Through the provision of state-of-the-art facilities, techniques and expertise, the Core enhances and encourages multidisciplinary research in the basic biology of aging at UM and worldwide.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Taxol (paclitaxel) is the one of the most widely used chemotherapy agents, and is a first-line treatment for ovarian, breast, lung, and colon cancer. Despite its well-documented anti-cancer properties, taxol is known to cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN affects approximately 30% - 50% of all chemotherapy patients, and the neuropathic pain can be so severe that in some cases, chemotherapy treatments must be discontinued. Therapeutic options for patients with CIPN are currently very limited, and so a new approach for mitigating the effects of CIPN could have a significant clinical impact. Naurex is investigating a new approach to addressing CIPN. The company has developed a novel class of non-toxic, orally bioavailable compounds that modulate the N-methyl D-aspartate receptor (NMDAR) within the glutamatergic system. The NMDAR is involved in regulation of synaptic plasticity, and it is known that neuropathic pain results in the dysregulation of synaptic plasticity. Our preliminary data shows that Naurex's NMDAR partial agonists display a dose-dependent analgesic effect in a rat Taxol model of CIPN. A lead compound, NRX-2922, was identified from these initial studies that displays desirable pharmaceutical properties in addition to excellent activity in the rat Taxol model. The scope of this Phase I SBIR project is to conduct pre-clinical studies to further evaluate the therapeutic potential of NRX-2922 for mitigating CIPN. To this end, our Specific Aims are: Aim #1 Establish dose response of NRX-2922. Aim #2 Evaluate NRX-2922's therapeutic potential for prevention and treatment of CIPN. Aim #3 Evaluate pharmacokinetics and toxicity of NRX-2922 in combination with Taxol. Successful completion of this Phase I project will establish effective dosing regimens of NRX-2922 that will inform follow-on IND enabling studies as well as clinical trial protocols. Given the widespread use of taxol, and its proven effectiveness as a chemotherapeutic agent, the potential to reduce the main side-effect associated with its usage would be highly significant in the field of oncology.
|
{
"pile_set_name": "NIH ExPorter"
}
|
In this competing renewal application, the Native Elder Research Center (NERC) seeks support for Program Years (PY) 16-20. NERC will retain its 3 Core components?an Administrative Core, a Native Investigator Development Program (NIDP), and an Analysis Core (previously known as the Methods and Measurement Core). Spero M. Manson, PhD, Distinguished Professor of Public Health and Psychiatry, and Director, Centers for American Indian and Alaska Native Health (CAIANH), Anschutz Medical Center, University of Colorado Denver (UCD), serves as Principal Investigator, co-directs NERC with Dr. Dedra Buchwald, MD, and heads the Administrative Core. Dr. Manson, a medical anthropologist, is American Indian (Pembina Chippewa) and is nationally recognized for his research and leadership in areas directly relevant to all aspects of this Resource Center for Minority Aging Research (RCMAR), particularly aging and health among Native elders. Dr. Buchwald, Professor of Medicine at the University of Washington (UW) and a specialist in Native health, directs the UW component of the Administrative Core. Together, the UCD and UW Administrative Core staffs provide direction and support, both day-to-day and long-term, to the other Cores. The specific aims of the Administrative Core are to: 1) support the logistical operations of each Core, including: a) monitor adherence to standard personnel policies and procedures that follow UCD, UW, tribal, and Federal guidelines; b) integrate fiscal procedures across Core activities and projects; c) supervise fiscal aspects of career development and research efforts and provide detailed budgetary information to Core Directors and staff; d) prepare and disseminate Core program materials; and e) maintain Local Area Networks with integrated software and hardware configurations. 2) stimulate, coordinate, and monitor activities across Cores, including: a) ensure regular communication and coordination of activities; b) compile and distribute administrative and research documents from Native Investigators (NIs), Core Directors, Core and other faculty, and external consultants; and c) frequent review of individual Core action plans for timeliness and appropriateness. 3) supervise implementation of key decisions related to the research strategy, including: a) develop and oversee the NI recruitment, selection, assignment, and evaluation processes; b) coordinate and review NERC/RCMAR faculty involvement in activities across Cores; c) formalize agreements with local agencies and community participants in Pilot Studies; d) oversee the administrative aspects of the NI Pilot Study plans, including review, approval, and monitoring of Pilot Study budgets and Institutional Review Board (IRB) approvals; and e) continue to seek collaborative links within Clinical and Translational Science Award (CTSA) recipients, other RCMAR centers, and other aging-related research scientists. 4) facilitate program planning and review, including: a) support the ongoing process and outcome evaluation of NERC; b) create verbal and written reports on NERC progress (e.g.. Program Emphases and Outcomes Report, continuation applications, special requests) for the RCMAR Coordinating Center and the National Institute on Aging; and c) maintain active collaborative links with the RCMAR Coordinating Center. 5) sustain and expand community outreach and engagement, including: a) support outreach to tribal colleges and universities; and b) participate in the planning, convening, and reporting of tribal and Indian Health Service (IHS)-sponsored community research conferences. We note that the mandated funding reductions have necessitated a series of changes in scope for the Administrative Core from previous program years. Between the 2nd and 3rd cycles, funding was reduced from $600,000/year to $500,000/year. That reduction forced us to absorb the functions of the Community Liaison Core, which had been an independent component of our Center in the initial 2 periods of support, within the Administrative Core. The additional reduction of support available for the 4th RCMAR cycle, to $400,000/year, requires further reductions in NERC's community outreach and engagement activities in order to ensure the integrity of the NIDP and Analysis Core efforts. Yet, we remain committed and realistic. The proposed Administrative Core staff, drawn from the UCD and UW partners in this renewal, will engage in a broad range of logistical operations (e.g., scheduling, communication, personnel matters, expenditures, and monitoring); coordination of efforts across all Cores through a Coordinating Committee comprised of the Core Directors; key strategic decisions, program planning and review; and community outreach and engagement.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.