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Molecular control of CD4 T cell ability to help B cells

CD4 T 细胞帮助 B 细胞能力的分子控制

基本信息

批准号：
10357910
负责人：
Deepak Angara Rao
金额：
$ 11.64万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357910
关键词：
Antibody Formation Autoantibodies Autoimmune Diseases Automobile Driving B-Lymphocytes BCL6 gene Bioinformatics Biometry Blood Blood Circulation CD4 Positive T Lymphocytes CRISPR/Cas technology CXCL13 gene Cell Differentiation process Cell Maturation Cell physiology Cells Clinical Communication Data Development Development Plans Diagnosis Disease Doctor of Philosophy Environment Faculty Gene Deletion Gene Expression Profile Genes Genetic Transcription Genomics Goals Helper-Inducer T-Lymphocyte Hospitals Human Immune response Immunology In Vitro Inflammatory Interruption Joints Learning Lentivirus Lupus Lymphocyte Biology Lymphoid Lymphoid Tissue Mediating Mentors Methods Molecular Names Nature Nuclear PRDM1 gene Pathologic Pathway interactions Patients Peripheral Phenotype Plasma Cells Population Population Control Positioning Attribute Production Regulation Research Research Personnel Research Training Resources Rheumatism Rheumatoid Arthritis Sampling Signal Transduction Stimulus Surface Synovial Cell Synovial Fluid Synovial Membrane Synovitis Systemic Lupus Erythematosus T cell differentiation T cell regulation T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Technology Therapeutic Tissue Sample Tissues Training Woman Work base career career development cytokine dimensional analysis experience high dimensionality lymphoid structures medical schools novel therapeutic intervention overexpression progenitor programmed cell death protein 1 receptor response skills tenure track transcription factor transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract: This proposal details a five-year research and training plan with a scientific focus on a newly discovered population of T cells, termed `T peripheral helper' (Tph) cells, that is markedly expanded in the joints of patients with rheumatoid arthritis. The candidate led a study that identified and defined this CD4+ T cell subset (Rao et al, Nature, 2017). Tph cells display a unique capacity to infiltrate inflamed tissues and drive B cell responses within the tissue. The long-term objective of the proposed study is to understand signals that regulate the development and function of Tph cells in the hope of discovering pathways that can be manipulated therapeutically to treat autoimmune diseases. The specific aims proposed here utilize three complementary approaches to evaluate the regulation of Tph cells. Aim 1 will determine conditions that drive human T cell differentiation towards a Tph cell phenotype. Aim 2 interrogates the control of Tph cell function by 3 compelling transcriptional regulators that are overexpressed in Tph cells. Aim 3 evaluates the developmental relationship of Tph cells in RA synovial tissue samples with other synovial T cell populations, including T follicular helper cells. Using a combination of mechanistic studies, patient-derived samples, and cutting-edge technologies, this study will provide the candidate with new training in several key aspects of human translational immunology. The candidate's immediate career development goals are to gain experience with bioinformatic and biostatistical analyses, interpretation of transcriptomic data, genomic manipulation of primary human cells, and scientific communication. A specific career development plan is described by both the candidate and the mentors: Dr. Michael Brenner MD, an expert in lymphocyte biology and synovial inflammation, and Dr. Soumya Raychaudhuri MD PhD, an expert in bioinformatics, capitalizing on the powerful resources at Brigham and Women's Hospital and Harvard Medical School. The candidate's long-term career goal is to attain a tenure- track faculty position pursuing research that integrates high-dimensional analyses of patient samples with detailed mechanistic analyses to develop new methods to diagnose and treat rheumatic diseases.

项目概要/摘要：该提案详细介绍了一项为期五年的研究和培训计划，其科学重点是新发现的一群T细胞，称为“T外周辅助”（Tph）细胞，在患者关节中显著扩增风湿性关节炎这位候选人领导了一项研究，确定并定义了这种CD 4 + T细胞亚群（Rao et 等人，Nature，2017）。Tph细胞显示出独特的能力，渗透发炎组织和驱动B细胞反应在组织内。这项研究的长期目标是了解调节神经元的信号。 Tph细胞的发育和功能，希望发现可以操纵的途径，治疗自身免疫性疾病。这里提出的具体目标利用三种互补的方法来评估Tph的调节细胞目的1将确定驱动人T细胞向Tph细胞表型分化的条件。目的 2询问Tph细胞功能的控制由3个引人注目的转录调节因子，在Tph细胞中。目的3评价类风湿关节炎滑膜组织中Tph细胞的发育关系，其他滑膜T细胞群，包括T滤泡辅助细胞。使用机制研究，患者来源的样本和尖端技术的组合，这项研究将在人类翻译免疫学的几个关键方面为候选人提供新的培训。的候选人的直接职业发展目标是获得生物信息学和生物统计学方面的经验转录组学数据的分析、解释、原代人类细胞的基因组操作，以及科学通信一个具体的职业发展计划是由候选人和导师描述：博士。 Michael Brenner医学博士，淋巴细胞生物学和滑膜炎症专家，Soumya博士 Raychaudhuri医学博士，生物信息学专家，利用布里格姆的强大资源，妇女医院和哈佛医学院。候选人的长期职业目标是获得终身职位- 跟踪教师职位追求的研究，整合患者样本的高维分析，详细的机制分析，以开发新的方法来诊断和治疗风湿性疾病。