权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of TNF in Breaking B Cell Tolerance

TNF 在破坏 B 细胞耐受性中的作用

基本信息

批准号：
10650371
负责人：
Tam D Quach
金额：
$ 12.77万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650371
关键词：
Acceleration Address Affect Affinity Age Agonist Amyloid fibers Anti-Inflammatory Agents Antibodies Antibody Formation Antibody-Producing Cells Antigen-Antibody Complex Antigens Antinuclear Antibodies Autoantibodies Autoimmune Autoimmunity B cell differentiation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Binding Biological CD22 gene Cardiolipins Cells Chromatin Clinical Clinical Research Computational Biology Computer Models Data Defect Demyelinating Diseases Development Development Plans Disease Drug usage Education Educational workshop Environment Escherichia coli Faculty Follicular Dendritic Cells Foundations Future Generations Goals Grant Homeostasis Human IL17 gene Immune response Immune system Immunologist In Vitro Individual Knowledge Ligands Lupus Mediating Medical Research Mentors Methodology Modeling Mus Opportunistic Infections Pathogenicity Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phenotype Postdoctoral Fellow Predisposition Pristane Process Production Psoriasis RNA Reagent Receptors, Tumor Necrosis Factor, Type II Regulation Research Research Activity Research Personnel Research Project Grants Resources Rheumatoid Arthritis Role SLEB1 gene Sampling Self Tolerance Signal Transduction Source Stimulus Structure Structure of germinal center of lymph node System Systemic Lupus Erythematosus T-Lymphocyte TLR2 gene TNF gene TNFRSF1A gene TNFRSF1B gene Technology Testing Training Training Activity United States Vasculitis Work attenuation autoreactive B cell autoreactivity career development chronic autoimmune disease cohort cytokine design drug development effective therapy effector T cell experience immunoregulation improved individual patient inhibitor insight instructor interleukin-21 member mouse model mutational status next generation sequencing novel personalized medicine predictive modeling prevent response restoration safe patient side effect skills

项目摘要

Dr. Quach's central goal is to acquire new skills that will establish her as a systems immunologist. The proposed research combines murine and human studies to identify mechanisms by which TNF deficiency breaks tolerance. The gained knowledge will guide future efforts in designing personalized medicine for autoimmune patients. Candidate: Dr. Quach is an instructor at the Feinstein Institute for Medical Research (FIMR). Through her Ph.D and post-doctoral work, she focused on the development and regulation of B cells in humans. The proposed career development plan will build upon her previous experience with four training goals to enhance her trajectory toward becoming an independent investigator: 1) gain expertise in utilizing mouse models; 2) become proficient in computational biology; 3) gain insights into conducting clinically oriented research projects, and 4) build a foundation of data and methodologies to generate predictive models. Mentors/Environment: Dr. Quach and her mentor, Dr. Anne Davidson, have assembled a strong team of advisors and collaborators to guide her through the proposed training and research activities. The proposed project utilizes the intellectual, research and clinical facilities available at the FIMR and the resources available through her external advisors and collaborators, Dr. Steven Kleinstein and Dr. Inaki Sanz. FIMR is committed to support junior faculty members through internal grants and opportunities for networking and education. Dr. Quach will attend national seminars/workshops when optimal training is not available locally. Research: The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well- known; however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans, TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice, TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and alters autoantibody profiles. This study proposes that TNF deficiency, together with a second inducing stimulus, compromises GC B cell selection via reduction of negative GC B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, to determine the mechanism for the signaling defect in GC B cells that alters B cell selection, and how T cells help to enhance this process. The second aim will address similar questions in TNFi treated patients using a novel fluorescent reagent to detect and isolate ANA reactive B cells combined with next generation sequencing technology. A combination of phenotyping and functional studies is used to determine T cells' influences. The results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our understanding of how the immune system regulates B cell tolerance when GC formation is abnormal.

Quach博士的中心目标是获得新的技能，这将使她成为一名系统免疫学家。提出的