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: 8926988
• 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/8926988
• 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; genetic approach; 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 na�ve 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：我获得此职业发展奖的目标是获得必要的培训，成为一名独立的医师科学家，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，获得了博士学位。免疫学研究 T 细胞受体基因组装的调节。随后，我开始对幼稚 T 细胞分化为 TH 亚群产生了特别的兴趣。基于分子遗传学的基础技能，我现在计划增加细胞免疫学、化学生物学和炎症动物模型方面的专业知识和指导研究经验，以进一步了解炎症性疾病背景下 Treg 的发育和功能。我的导师是 IBD 遗传学和生物学领域的免疫学家领导者，他提供了一个无与伦比的环境，非常适合这个项目和我的职业生涯的成功。我的研究咨询委员会带来了所有必要的额外专业知识，我的监督委员会由成功的研究人员组成，他们都是优秀的导师。我之前的研究和临床培训，以及获奖期间的指导研究和课程作业，将培养我的基本技能，并强调 Treg 分化调节方面的重要发现，我将作为一名独立的、由 R01 资助的研究人员进行后续研究，长期目标是了解 T 细胞生物学在炎症性疾病背景下是如何调节的。项目：Treg 细胞是重要的抗炎细胞，其发育和/或功能受损会导致炎症性疾病。新数据显示，Tregs 通常表现出器官特异性的特化，以促进与生态位相关的作用，这让人质疑当前离体扩展 Tregs 的方法是否能够充分重现此类功能。我假设局部微环境包含诱导利基特定功能所需的专业化所需的线索。我们开创性的公正的化学生物学工作确定了 Treg 分化的新型小分子增强剂，包括去氢骆驼蓬碱和来自 Broad DOS 系列的 2 个支架。具体目标 1 中描述的实验流程重点介绍了基于这些支架的优化增强剂。 Harmine 和优化的 DOS 增强剂用于解决特定目标 2 中的核心假设，即在稳态和使用炎症体内模型时，将小分子 Treg 增强剂递送至粘膜表面可促进局部和远端的 Treg 发育和功能。在具体目标 3 中，我们讨论了去氢骆驼蓬碱试点研究提出的新颖且可测试的机制假设，包括谱系可塑性，以及新候选基因（DYRK1a 和 DYRK2）和通路（Creb 和 NF-kB1 信号传导）在 Treg 分化中的作用。这些研究对基于 Treg 的治疗的概念方法具有重要影响，并可能突出 Treg 分化的新调节因子，并指出快速生成机制假设的多学科方法，增强我们对炎症性疾病背景下 Treg 生物学的基本理解。