Mucosal and systemic circuits regulating Treg differentiation and function

描述(由申请者提供)：候选人/培训：我的职业发展奖的目标是获得必要的培训，成为一名独立的内科医生和科学家，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，获得了免疫学博士学位，研究T细胞受体基因组装的调节。随后，我开始对NA�ve T细胞分化为TH亚群产生特殊兴趣。在分子遗传学基本技能的基础上，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Treg在炎症性疾病背景下的发育和功能。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，非常适合这个项目的成功和我的职业生涯。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调查人员组成，他们是优秀的导师。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工作，将培养基本技能，并突出Treg分化调控方面的重要发现，我将作为一名独立的、R01资助的研究人员进行跟踪，长期目标是了解T细胞生物学是如何在炎症性疾病的背景下调节的。项目：Treg是关键的抗炎细胞，其发育和/或功能受损会导致炎症性疾病。新出现的数据显示，Tregs通常表现出器官特异性的特化，以促进与利基相关的角色，这引发了人们对目前在体外扩大Tregs的方法是否能够充分复制这些功能的质疑。我假设，当地的微环境包含诱导特定利基功能所需的专业化所需的线索。我们开创性的、不偏不倚的化学生物学努力确定了新型的Treg分化小分子增强剂，包括骆驼蓬碱和远大DOS系列中的2个支架。在特定目标1中描述的实验流水线突出了基于这些支架的优化增强剂。骆驼蓬碱和优化的DOS增强剂用于解决特定目标2的核心假设，即将小分子Treg增强剂输送到粘膜表面促进Treg的发育和局部和远端功能，无论是在稳定状态下还是使用体内炎症模型。在具体目标3中，我们提出了新的和可验证的机制假说，包括对骆驼蓬碱的初步研究，包括谱系可塑性，以及新的候选基因(DYRK1a和DYRK2)和通路(CREB和NF-Kb1信号)在Treg分化中的作用。这些研究对基于Treg的治疗的概念性方法具有重要影响，并可能突出Treg分化的新调节因素，以及指向多学科方法以快速生成机制假说，增强我们在炎症性疾病背景下对Treg生物学的基本理解。

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.