Function of microRNAs in controlling regulatory T cell biology

总结 维持正常的Foxp 3+调节性T（Treg）细胞稳态和抑制功能对于维持正常的Foxp 3+调节性T（Treg）细胞的稳态和抑制功能是至关重要的。 建立免疫耐受性。最近，一类短的调节性非编码RNA也被称为 microRNA（miRNAs）在Treg细胞的发育和功能中起关键作用。最近我们 显示选择性地切除Treg细胞中的miRNA导致自身免疫性致死性的早期发作， 与在缺乏Treg细胞的小鼠中观察到的那些不可区分。不同的miRNA表达谱， Treg细胞中的Foxp 3直接靶向这些基因，进一步表明特异性miRNAs可以控制Treg细胞中Foxp 3的表达。 Treg生物学的不同方面。为此，Foxp 3驱动的miR-155是维持正常Treg细胞所必需的。 正如我们之前的研究所证明的那样。在本申请中，我们已经表明高miR-146 a 在Treg细胞中的表达对于通过靶向信号转导子有效控制TH 1应答是必需的 和转录激活因子1（STAT 1）。Treg细胞中miR-146 a的缺失导致两种总RNA水平的增加。 和磷酸化STAT 1。因此，具有miR-146 a缺陷Treg细胞的小鼠死于 IFN依赖型I免疫病理学。我们目前的研究结果提供了强有力的证据表明， 除了Treg细胞中的稳态外，Treg抑制功能也可以由单个miRNA调节。这 这项工作进一步表明，依赖于miRNA的转录后调节使Treg细胞能够控制细胞的增殖。 特定类型的效应T细胞反应。 我以前的研究涉及采用广泛的分子和细胞手段来研究两者 体液和细胞免疫应答，通过各种未操作的小鼠品系， 包括同种异体移植和不同肿瘤系统的临床适用模型。在鲁登斯基博士的 目前的指导和纪念斯隆-凯特琳癌症提供的丰富和资源丰富的环境 中心和其他成员在三机构生物医学研究社区，包括威尔康奈尔医疗 学院和洛克菲勒大学，我提出了一个多方面的研究，利用遗传，生物化学， 免疫学方法和整体动物实验来检查miRNA依赖性的作用， Treg细胞介导的免疫耐受中的转录后调节。与全面的 职业发展计划，包括建立机构内和机构间合作和继续培训 和教育，这些因素无疑将促进我向独立研究的过渡，并应允许 我成为一个在世界顶级研究机构之一的知名研究员。

Summary Maintaining normal Foxp3+ regulatory T (Treg) cell homeostasis and suppressive function is essential for establishing immunological tolerance. Recently, a class of short regulatory non-coding RNAs also called as microRNAs (miRNAs) are shown to be pivotal in the development and function of Treg cells. Recently we have shown that selectively ablation of miRNAs in Treg cells resulted in the early onset of autoimmune lethality indistinguishable to those that were observed in mice devoid of Treg cells. Distinct miRNA expression profiles, of which many were directly targeted by Foxp3 in Treg cells further suggested specific miRNAs could control different facets of Treg biology. To this end, Foxp3-driven miR-155 is required for maintaining normal Treg cell homeostasis as demonstrated in our previous study. In this application, we have shown that high miR-146a expression in Treg cells is essential for effective controls of TH1 responses through targeting signal transducer and activator transcription 1 (STAT1). Loss of miR-146a in Treg cells resulted in increased levels of both total and phosphorylated STAT1. As a consequence, mice with miR-146a deficient Treg cells succumbed to IFN¿-dependent type I immunopathology. Our current results provided strong evidence suggesting that, in addition to homeostasis in Treg cells, Treg suppression function could also be regulated by a single miRNA. This work further implied that miRNA-dependent post-transcriptional regulation enables Treg cells to control a particular type of effector T cell responses. My previous research involved employing a wide spectrum of molecular and cellular means to study both humoral and cellular immune responses through both a variety of unmanipulated mouse strains and clinical-applicable models including allograft transplantation and different tumor systems. Under Dr. Rudensky's current mentoring and with the rich and resourceful environment provided by Memorial Sloan-Kettering Cancer Center and other members in the Tri-institutional biomedical research community including Weill Cornell Medical College and The Rockefeller University, I propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to examine the role of miRNA-dependent post-transcriptional regulation in Treg cell-mediated immunological tolerance. Together with a comprehensive career development plan, including establishing intra- and inter-institutional collaborations and continued training and education, these elements will undoubtedly facilitate my transition to independent research and should allow me to become a well-established investigator in one of the world's top-research institutes.