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BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10337030
负责人：
GAIL A. BISHOP
金额：
--
依托单位：
IOWA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-10-01 至 2027-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337030
关键词：
Abnormal Cell Adaptor Signaling Protein Age Aging Antibodies Area Autoimmunity Award B lymphoid malignancy B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes Basic Science Biological Biological Markers Blood Cell Aging Cell Surface Receptors Cell Survival Cells Characteristics Chronic Clinic Clinical Clinical Trials Collaborations Communicable Diseases Communities Community Participation Development Disease Doctor of Philosophy Ebola virus Educational process of instructing Ensure Event Funding Future General Population Genes Genetic Transcription Glucose Goals Graft Rejection Grant Review Health Human Human Herpesvirus 4 Immune Immune response Immunity Industry Infection Inflammatory Interleukin 6 Receptor Interleukin-6 International Intervention Investigation Iowa Knowledge LMP1 Laboratories Leadership Leukocytes Life Lymphocyte Lymphocyte Biology Lymphocyte Function Lymphoma Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Measures Mediating Medical Mentors Metabolism Molecular Monoclonal Antibodies Mouse Strains Multiple Myeloma Mus Mutation Nature Nuclear Protein Oncogenic Oncologist PTPN22 gene Pathogenesis Pathway interactions Phenotype Phosphoric Monoester Hydrolases Physicians Play Population Post-Translational Protein Processing Predisposition Preparation Process Progress Reports Proteins Publications Regulation Research Research Personnel Resistance Role Scientific Societies Scientist Services Signal Transduction Signaling Protein Source Specialist T-Lymphocyte TNFRSF1A gene TNFRSF5 gene Therapeutic Toxin Translating Translations Tumor Necrosis Factor Receptor Tumor Suppressor Proteins Tumor-Derived Universities Veterans Virus Diseases Work c-myc Genes cancer cell cancer therapy career cell killing cell type clinical application clinically relevant effective therapy fighting genetic regulatory protein glucose metabolism glucose uptake improved inhibitor insight interest loss of function military veteran neoplastic cell news next generation prevent programs protein function receptor recruit service organization small molecule inhibitor treatment trial tumor

项目摘要

The overall research program of the applicant seeks to develop new insights and understanding of the key molecular mechanisms regulating the functions of, and interactions between immune cells, with a particular emphasis on B and T lymphocytes, and B cell-derived tumors. The ultimate goal is to apply this knowledge to development of improved measures to both prevent and treat diseases involving lymphocytes, as well as to inform the clinical selection of the optimal available treatments for a specific Veteran's tumor. The basic science investigations that began in the applicant's laboratory 30 years ago are now leading to important collaborations with physician-scientists to translate the findings of these studies into treatments and clinical trials. The projects to be pursued during the proposed funding period of this SRCS award, and their relevance to Veteran health, include the following. 1) Define the role of the signaling protein TNF Receptor Associated Protein 3 (TRAF3) as a tumor suppressor in B cell cancers. B cell lymphoma (BCL) and multiple myeloma (MM), the most common cancers of lymphocytes in humans, are over-represented in the Veteran population. In both BCL and MM, loss-of-function TRAF3 mutations are common, and the applicant discovered that post-translational loss of TRAF3 protein can also occur. The proposed project will continue to define how TRAF3 restrains survival pathways which, when dysregulated, contribute to BCL/MM pathogenesis, define how TRAF3 regulates BCL metabolism, determine the mechanisms and biological consequences of post-translational loss of TRAF3 protein in the B cells of aging humans, and develop new biomarkers for MM-initiating cells. Importantly, all these projects will involve ongoing collaborations with clinician colleagues. 2) Determine clinically-relevant roles of TRAF3 in other immune cell types. The applicant's lab will continue studies revealing how TRAF3 enhances and regulates the function of T lymphocytes, critical to human immune responses to infectious disease and tumors. A new project, in collaboration with two physician-scientists, investigates the consequences of monoallelic TRAF3 disruption in humans, leading to chronic susceptibility to infections, and autoimmunity. We strongly suspect that this genetic defect is in fact much more widespread than previously appreciated. 3) Translate the applicant's knowledge of CD40 function into clinical application. This involves projects that seek to optimize an antagonistic anti-human CD40 antibody for use in blocking transplant rejection, a clinical problem of relevance to Veterans, and to understand the protective role played by CD40 in resistance to Ebola virus infection. 4) Provide key expertise in B lymphocyte biology to funded collaborative projects in MM and pancreatic cancer. Both these malignancies occur at higher-than-normal rates in the Veteran population. In addition to these 4 major project areas, which form the major research Aims, the applicant will continue her strong commitment and activities in mentoring and teaching the next generation of biomedical researchers, both PhD and MD, and serve the scientific community in committee participation, review of grants and manuscripts, and leadership roles in scientific societies.

申请人的整体研究计划寻求发展新的见解和理解的关键