Function of human regulatory cells in the intestinal mucosa of humanized mice

描述（由申请人提供）：候选人拥有博士学位。他对基础科学研究有着极其坚定的承诺，对胃肠道粘膜免疫学特别感兴趣。该奖学金的候选人短期目标是1）精通免疫学，使用生物化学和遗传技术研究免疫介导的病理机制; 2）获得概念和技术前沿方法的专业知识，以实验设计，可以阐明人类调节性T细胞在肠道炎症中的作用; 3）培养专业经验，促进免疫学，上皮生物学和微生物学专家之间的创造性和高度跨学科合作; 4）提供足够的初步数据和出版物，作为竞争性K 01申请的基础。候选人的长期职业目标是成为一名独立资助的研究人员，并为我们的胃肠道粘膜免疫学知识做出有意义的贡献，以造福人类健康。该项目的总体主题是了解人类调节性T细胞在肠道粘膜中发挥作用以促进免疫稳态的机制和要求。研究表明，在小鼠和人类中，TdR是效应T细胞应答的关键负调节因子。对于免疫介导的疾病和免疫缺陷，Treg功能障碍与疾病的发病机制和发病率相关。虽然实验数据暗示了鼠TdR在粘膜稳态中的作用，但由于对人类受试者的实验和对相关组织的获取的限制，对人类TdR在肠道炎症期间的作用的了解还没有得到很好的表征。为了解决这个问题，我们将利用能够移植人白细胞的小鼠模型，使用两种实验性T细胞介导的肠道炎症模型，抗CD 3介导的小肠肠病和TNBS介导的结肠炎症，来检查Tclase在肠道炎症过程中的作用。本研究的具体目标是检验以下假设：人T细胞在外源性系统中以TGF-β和IL-10依赖性方式抑制人T细胞介导的肠道炎症。拟议的工作将在密集和正式的职业发展计划的背景下进行，这将使候选人获得经典和前沿免疫学和细胞生物学方法的专业知识，以研究肠道免疫稳态。此外，还将建立一个由波士顿儿童医院和哈佛医学院的研究人员组成的多元化小组，他们在免疫调节和粘膜免疫学方面具有专长，以监督候选人的进展。研究环境将提供一个智力丰富，技术资源丰富和协作的氛围，将催化候选人的科学生产力。在奖励期结束时，候选人将很好地定位为一个独立的K 01奖的申请人。

DESCRIPTION (provided by applicant): The candidate holds a Ph.D. with an extremely strong commitment to basic science research, and a specific interest in gastrointestinal mucosal immunology. The candidates short-term goals for this fellowship are 1) to become proficient in immunology using biochemical and genetic techniques to investigate mechanistically immune-mediated pathologies; 2) to acquire expertise in conceptually and technologically cutting-edge approaches to experimental design that can elucidate the role of human regulatory T cells in intestinal inflammation; 3) to develop professional experience in fostering creative and highly interdisciplinary collaborations between experts in immunology, epithelial biology and microbiology; 4) to produce sufficient preliminary data and publications that will serve as the basis for a competitive K01 application. The candidate's long-term career goal is to become an independently funded investigator and make meaningful contributions to our knowledge of gastrointestinal mucosal immunology to benefit human health. The overall theme of this project is to understand the mechanisms and requirements by which human regulatory T cells function in the gut mucosa to promote immune homeostasis. Studies implicate Tregs as critical negative regulators of effector T cell responses in both mice and humans. For immune-mediated diseases and immunodeficiencies, Treg dysfunction is associated with disease pathogenesis and morbidity. While experimental data implicate a role for murine Tregs in mucosal homeostasis, insight into the role of human Tregs during intestinal inflammation is not well characterized due to restrictions on experimenting with human subjects and access to relevant tissues. To address this problem, we will utilize a mouse model capable of engrafting human leukocytes to examine the role of Tregs during intestinal inflammation using two experimental T cell-mediated models of intestinal inflammation, anti-CD3-mediated small intestinal enteropathy and TNBS-mediated colonic inflammation. The specific goal of this study is to test the hypotheses: Human Tregs function in a xenobiotic system to suppress human T cell-mediated intestinal inflammation in a TGF-beta and IL-10 dependent manner. The proposed work will be pursued within the context of an intensive and formalized career development program, which will allow the candidate to acquire expertise in both classic and leading edge immunology and cell biological approaches to studying intestinal immune homeostasis. In addition, a diverse group of researchers at Children's Hospital Boston and Harvard Medical School with expertise in immune regulation and mucosal immunology will be established to oversee the candidate's progress. The research environment will provide an intellectually enriching, technically resourceful and collaborative atmosphere that will catalyze the candidate's scientific productivity. At the conclusion of the award period, the candidate will be well positioned as an applicant for an independent K01 award.