Molecular control of CD4 T cell ability to help B cells

项目摘要/摘要： 该提案详细说明了一项为期五年的研究和培训计划，该计划的科学重点是一项新发现的 T细胞群，称为‘T外周辅助’(TPH)细胞，在患者的关节中显著扩张 患有类风湿性关节炎。这位候选人领导了一项研究，确定并定义了这个CD4T细胞亚群(RAO ET 阿尔，自然，2017)。TPH细胞表现出独特的渗透炎症组织和驱动B细胞反应的能力 在组织内。这项拟议研究的长期目标是了解调节 TPH细胞的发育和功能，希望发现可以操纵的途径 用于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的监管 细胞。目的1将确定促使人类T细胞分化为TPH细胞表型的条件。目标 2通过3个令人信服的过度表达的转录调节因子来询问对TPH细胞功能的控制 在TPH细胞中。目的评价RA滑膜组织标本中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。 这项研究结合了机械学研究、患者样本和尖端技术 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。这个 应聘者近期的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 分析、解释转录数据、人类原代细胞的基因组操作，以及科学 沟通。候选人和导师都描述了一个具体的职业发展计划： 迈克尔·布伦纳医学博士，淋巴细胞生物学和滑膜炎症专家，苏米亚博士 生物信息学专家Raychaudhuri医学博士，利用Brigham和 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教职- 跟踪从事研究的教师职位，该研究将患者样本的高维分析与 详细的机理分析，以开发诊断和治疗风湿病的新方法。

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.