Mucosal and systemic circuits regulating Treg differentiation and function

调节 Treg 分化和功能的粘膜和全身回路

• 批准号: 8805065
• 负责人: Bernard Khor
• 金额: $ 15.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805065
• 关键词: Address; Adipose tissue; Advisory Committees; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autoimmunity; Award; Biology; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Line; Cell-Mediated Cytolysis; Cells; Cellular Immunology; Cellular biology; Chemicals; Clinical; Colitis; Collection; Colon; Complex; Cues; Data; Development; Disease; Distal; Distant; Doctor of Philosophy; Drug Kinetics; Enhancers; Environment; Equilibrium; Exhibits; Family; Funding; Gastrointestinal tract structure; Generations; Genetic; Goals; Granzyme; Harmine; Health; Homeostasis; Homing; Human; Immune; Immune response; Immunity; Immunologist; Immunology; In Vitro; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-17; Intestines; K-Series Research Career Programs; Lamina Propria; Libraries; Link; Maps; Mediating; Medicine; Mentors; Metabolic; Metabolism; Mixed Lymphocyte Culture Test; Modeling; Molecular Genetics; Molecular Profiling; Mouse Strains; Mucosal Immunity; Mus; Muscle; Oral Administration; Organ; Pathway interactions; Patients; Phosphotransferases; Physicians; Pilot Projects; Play; Production; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Role; Scientist; Series; Severities; Signal Transduction; Site; Small Intestines; Solutions; Stomach; Surface; Surveys; Syndrome; System; T cell differentiation; T-Cell Receptor Genes; T-Lymphocyte; Testing; Training; Transfusion; Treatment Efficacy; Visceral; base; career; chemical genetics; cytokine; experience; extracellular; follow-up; in vivo; in vivo Model; indexing; interdisciplinary approach; interest; novel; peripheral tolerance; reconstitution; repaired; research study; scaffold; screening; skills; small molecule; success

DESCRIPTION (provided by applicant): CANDIDATE/TRAINING: My goal for this career development award is to obtain the necessary training to become an independent physician-scientist studying novel circuits that control regulatory T cell (Treg) differentiation and functio. I am a transfusion medicine fellow who earned a Ph.D. in Immunology studying the regulation of T cell receptor gene assembly. Subsequently, I began pursuing a specific interest in the differentiation of naive T cells into TH subsets. Building on foundational skills in molecular genetics, I now plan to add expertise and mentored research experience in cellular immunology, chemical biology and animal models of inflammation to further our understanding of Treg development and function in the context of inflammatory disease. My mentor is an immunologist leader in IBD genetics and biology and provides an unparalleled environment uniquely suited to the success of this project and my career. My research advisory committee brings all necessary additional expertise and my oversight committee comprises successful investigators who are excellent mentors. My prior research and clinical training, together with mentored research and coursework during the award period will build fundamental skills and highlight important findings in the regulation of Treg differentiation that I will follow up as an independent, R01-funded investigator with the long-term goal of understanding how T cell biology is modulated in the context of inflammatory disease. PROJECT: Tregs are critical anti-inflammatory cells, impaired development and/or function of which leads to inflammatory disease. Emerging data shows that Tregs typically exhibit organ-specific specializations to facilitate niche-relevant roles, calling nto question whether current approaches to expand Tregs ex vivo can adequately reproduce such functions. I hypothesize that local microenvironments contain the cues necessary to induce specializations required for niche-specific functions. Our pioneering unbiased chemical biology efforts identified novel small molecule enhancers of Treg differentiation, including harmine and 2 scaffolds from the Broad DOS collection. The experimental pipeline described in Specific Aim 1 highlights optimized enhancers based on these scaffolds. Harmine and the optimized DOS enhancers are used to address the core hypothesis in Specific Aim 2, that delivery of small molecule Treg enhancers to mucosal surfaces promotes Treg development and function locally and distally, both at steady state and using in vivo models of inflammation. In Specific Aim 3, we address novel and testable mechanistic hypotheses raised by pilot studies with harmine, including lineage plasticity, as well as the role of novel candidate genes (DYRK1a and DYRK2) and pathways (Creb and NF-kB1 signaling) in Treg differentiation. These studies have important impact on the conceptual approach to Treg-based therapy and are likely to highlight novel regulators of Treg differentiation, as well as point to multidisciplinary approaches to rapidly generate mechanistic hypotheses, enhancing our basic understanding of Treg biology in the context of inflammatory disease.

描述（由申请人提供）：候选人/培训：我获得职业发展奖的目标是获得必要的培训，成为独立的医师科学家，研究控制调节性T细胞（TREG）分化和功能的新型电路。我是一名输血医学研究员，获得博士学位。在研究T细胞受体基因组装调节的免疫学中。随后，我开始对幼稚T细胞分化为TH子集的特定兴趣。我现在计划在分子遗传学领域的基础技能上增加专业知识，并指导了细胞免疫学，化学生物学和动物炎症模型的研究经验，以进一步了解我们对炎症性疾病中Treg发育和功能的理解。我的导师是IBD遗传学和生物学领域的免疫学家，并为该项目和我的职业生涯的成功提供了一个无与伦比的环境。我的研究咨询委员会带来了所有必要的其他专业知识，而我的监督委员会组成了一个成功的调查员，这些调查员是出色的导师。我先前的研究和临床培训以及奖励期间的指导研究和课程工作将建立基本技能，并在调节Treg差异化中的重要发现，我将作为一名独立的R01资助的研究者进行跟进，其长期目标是了解如何在炎症性疾病的情况下对T细胞生物学进行调节。项目：Treg是关键的抗炎细胞，发育受损和/或功能导致炎症性疾病。新兴数据表明，Treg通常表现出特定器官特定的专业知识，以促进与利基相关的角色，呼吁n询问当前扩展Tregs的方法是否可以充分地扩展Tregs的方法。我假设局部微环境包含诱导特异性功能所需的专业知识所必需的线索。我们开创性的无偏化化学生物学工作确定了Treg分化的新型小分子增强子，包括Harmine和2个来自广泛的DOS收集的支架。特定目标1中描述的实验管道突出显示了基于这些支架的优化增强剂。 Harmine和优化的DOS增强子用于解决特定目标2中的核心假设，即在稳态下以及使用体内炎症模型，将小分子Treg增强子递送到粘膜表面促进了Treg的开发和局部和远端的功能。在特定的目标3中，我们介绍了通过Harmine的试验研究提出的新颖和可检验的机械假设，包括谱系可塑性，以及新型候选基因（Dyrk1a和Dyrk2）的作用（DYRK1A和DYRK2）以及途径（CREB和NF-KB1信号）在TREG差异中。这些研究对基于TREG治疗的概念方法有重要影响，并可能会突出treg分化的新调节剂，以及对迅速产生机械假设的多学科方法的指向，从而增强了我们对炎症性疾病背景下Treg生物学的基本理解。