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

基本信息

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
项目类别：
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

项目摘要

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。获得免疫学博士学位的医学研究员，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。除了分子遗传学的基础技能之外，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。 IBD 遗传学和生物学，并提供了一个无与伦比的环境，独特地适合该项目和我的职业生涯，我的研究咨询委员会提供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，他们是我之前的研究和临床导师培训，与指导者一起奖励期间的研究和课程作业将培养基本技能并突出 Treg 分化调节方面的重要发现，我将作为一名独立的、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 Treg 分化调节中的调节方式项目：Tregs 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。目前体外扩增Tregs的方法是否能够充分复制这些功能，我热切地希望局部微环境包含诱导特定生态位功能所需的专门化线索，我们开创性的公正的化学生物学工作发现了Tregs分化的新型小分子增强剂，包括去氢骆驼蓬碱。 Specific Aim 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子，并且优化的 DOS 增强子用于解决 Specific Aim 中的核心假设。如图 2 所示，将小分子 Treg 增强剂递送至粘膜表面可促进局部和远端 Treg 的发育和功能，无论是在稳态还是使用体内炎症模型。在具体目标 3 中，我们提出了通过试点研究提出的新颖且可测试的机制假设。这些研究包括去氢骆驼蓬碱，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。对基于 Treg 的治疗的概念方法产生重要影响，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。