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Mechanistic insights into factor VIII inhibitor formation and eradication

对因子 VIII 抑制剂形成和根除的机制见解

基本信息

批准号：
10641791
负责人：
Bhavya Sharad Doshi
金额：
$ 15.52万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641791
关键词：
Acquired Immunodeficiency Syndrome Address Advisory Committees Affinity Animal Model Antibodies Antibody Response Antibody Therapy Antigens Autoimmune Diseases Award B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Basic Science Beta Cell Biological Markers Blood Blood Coagulation Disorders Bypass CD4 Positive T Lymphocytes Career Choice Cell Maturation Cells Cementation Chronic Clinic Coagulation Factor Deficiency Coagulation Process Cytokine Gene Data Dendritic Cells Dependence Development Disease Dose Educational workshop Equilibrium F8 gene Factor VIII Fibroblasts Fostering Functional disorder Future Generations Genetic Genetic Polymorphism Genomics Genotype Goals Helper-Inducer T-Lymphocyte Hematological Disease Hematopoietic Hemophilia A Hemorrhage Hemostatic function Homeostasis Human Immune Immune Tolerance Immune response Immunization Immunize Immunoglobulin Somatic Hypermutation Immunologics Immunology In Vitro Infusion procedures Inherited Interleukin-10 Investigation Isoantibodies Joints Kinetics Learning Licensing Location MS4A1 gene Marrow Mature B-Lymphocyte Memory Memory B-Lymphocyte Mentors Methods Morbidity - disease rate Mus Mutation Pathogenesis Patients Persons Pharmaceutical Preparations Phenotype Physicians Plasma Cells Population Predisposing Factor Prevention strategy Proliferating Quality of life Research Research Proposals Role Sampling Science Scientist Secondary to Series Source Structure of germinal center of lymph node Susceptibility Gene T cell response T-Lymphocyte TNF gene Therapeutic Training Training Programs Translating Translational Research Variant Work anti-CD20 arthropathies belimumab biobank career career development cytokine enzyme replacement therapy experience hands on research immunogenicity immunomodulatory strategy immunomodulatory therapies improved in vivo inhibitor inhibitor therapy insight member migration mortality mouse model neutralizing antibody novel novel marker pre-clinical predictive marker prevent recruit response secondary lymphoid organ skills targeted treatment tissue culture translational physician treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT This K99 Career Pathway to Independence in Blood Science Award details a five-year training program to advance Dr. Bhavya Doshi’s career goal of becoming an independent translational physician-scientist in coagulation. The proposed application combines approaches using tissue culture and animal models with investigations using patient samples to address the current limitations in the understanding of the immune response to factor VIII (FVIII). Dr. Doshi’s career development and training objectives are geared to foster this research proposal and her overall career goal of understanding basic mechanisms that drive disease to develop targeted treatment and prevention strategies. During the award period, Dr. Doshi will engage with a robust team of scientists in hemostasis and immunology to build her immunologic and translational research skills, learn genomic skills necessary for her future career aspirations, and continue to develop her expertise in coagulation and inhibitors. Under the guidance of her mentors, Dr. Rodney Camire and Dr. Michael Milone, these training objectives will be met by a combination of didactic course work and workshops, participation in seminar series, hands-on research experience, and mentoring by her advisory committee. Her advisory committee is composed of world-renowned scientists with extensive mentoring experience and diverse and complementary scientific expertise. They are all versed in bringing basic research findings to the bedside. Hemophilia A (HA) is caused by a mutation in the F8 gene leading to dysfunction or deficiency of coagulation FVIII. The development of neutralizing antibodies (“inhibitors”) to FVIII is the leading cause of morbidity and mortality in patients with HA. Dr. Doshi’s preliminary studies in HA patients and mice are the first to support that the cytokine B cell activating factor (BAFF) is potentially a biomarker and/or regulator of the FVIII immune response. This proposal seeks to probe basic mechanisms in FVIII-specific B cell generation and how BAFF contributes to this humoral response in order to leverage these findings for therapeutic application. Aim 1 seeks to determine the location, kinetics, and types of B cell responses to FVIII in mice by using a novel method to identify FVIII-specific B cells and subsequently determine what happens to this compartment with immunomodulatory strategies, including anti-BAFF. As BAFF is both systemically and locally produced by fibroblast cells and hematopoietically-derived immune cells, respectively, Aim 2 investigates the source of BAFF and its effect on the T cell response to FVIII. Finally, Aim 3 assesses whether genetic drivers of cytokine levels for BAFF or T helper cytokines drive phenotypic changes in T and B cell subsets that lead to inhibitor generation and/or persistence in HA patients. Together, these studies will inform the immune compartments that are critical to the FVIII immune response and establish the preclinical data to translate anti-BAFF therapy to the clinics. The research and career objectives in this proposal will bolster Dr. Doshi’s research repertoire to enable her transition to an independent physician scientist focused on blood disorders, specifically hemophilia.

项目总结/文摘