Mucosal and systemic circuits regulating Treg differentiation and function

描述（由申请人提供）：候选人/培训：这个职业发展奖的目标是获得必要的培训，成为一个独立的医生，科学家研究控制调节性T细胞（Treg）分化和功能的新电路。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亚群产生了特殊的兴趣。基于分子遗传学的基础技能，我现在计划在细胞免疫学，化学生物学和炎症动物模型方面增加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遗传学和生物学的免疫学家领导者，并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，以及在奖励期间的指导研究和课程将建立基本技能，并强调调节Treg分化的重要发现，我将作为一名独立的，R 01资助的研究人员进行随访，长期目标是了解T细胞生物学如何在炎症性疾病的背景下调节。项目：胸腺是关键的抗炎细胞，其发育和/或功能受损导致炎症性疾病。新出现的数据表明，Tendon通常表现出器官特异性的专业化，以促进利基相关的作用，呼吁质疑目前的方法来扩大Tendon离体可以充分再现这些功能。我假设，当地的微环境包含必要的线索，诱导所需的利基特定功能的专业化。我们开创性的无偏化学生物学工作鉴定了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集合的2种支架。具体目标1中描述的实验管道突出了基于这些支架的优化增强子。去氢骆驼蓬碱和优化的DOS增强子用于解决特定目标2中的核心假设，即在稳态和使用体内炎症模型时，将小分子Treg增强子递送至粘膜表面促进局部和远端的Treg发育和功能。在具体目标3中，我们解决了由去氢骆驼蓬碱的初步研究提出的新的和可检验的机制假设，包括谱系可塑性，以及新的候选基因（DYRK 1a和DYRK 2）和途径（Creb和NF-kB 1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，并且可能突出Treg分化的新型调节剂，以及指向多学科方法以快速生成机制假说，增强我们对炎症性疾病背景下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.