MicroRNA regulation of Th17 cell differentiation

 描述（由申请人提供）哮喘是一种慢性炎症性气道疾病，目前在美国每12个成年人中就有1人受到影响。辅助性T（Th）细胞是通过分泌炎性细胞因子和募集其他免疫细胞来协调哮喘中的肺部炎症反应的免疫细胞。虽然Th 2细胞亚群在哮喘中最常被研究，但Th 17细胞也与至少一些哮喘亚型的疾病发病机制有关。Th 17细胞介导抗细菌和抗真菌免疫，它们与自身免疫性疾病明显相关，但它们在哮喘发病机制中的确切作用仍知之甚少。拟议的工作旨在阐明microRNAs（miRNAs）对Th 17细胞的调节，以更好地了解它们在哮喘等疾病中的失调。miRNA已经成为免疫细胞分化和功能的许多方面的重要调节因子。活化的T辅助细胞的细胞命运决定对调节因子的精确剂量特别敏感，因此受到miRNA的微调活性的调节。最近的研究表明，miR-17~92簇抑制了T滤泡辅助细胞（TFH）中亚群不适当基因的表达。相反，miR-17~92如何调节Th 17细胞的分化和功能仍不清楚。本研究的主要目的是通过气道实验来探讨miR-17~92簇在体外Th 17细胞分化中的作用及其在哮喘中的潜在功能意义 炎症模型目的1将联合收割机结合miR-17~92条件性基因敲除小鼠的应用和对簇内单个miRNAs的操作，通过体外和体内检测Th 17驻留组织来阐明这些miRNAs在调节Th 17细胞分化中的作用。初步数据表明，miR-17~92抑制Th 17细胞分化，这与其在Th 1、Th 2和TFH细胞中的作用相反。目的2探讨miR-17~92簇miRNAs靶向控制Th 17细胞生物学的基因表达网络的机制。最后，目标3将使用气道炎症模型确定miRNA调节Th 17细胞在哮喘中的影响。这项工作将提供有价值的见解的分子事件，管理Th细胞的命运决定和可塑性及其在一个常见的慢性炎症性疾病的影响。此外，这项工作可能有助于确定更具体的治疗方法，并改善哮喘亚表型患者的预后，其中Th 17细胞在炎症反应中发挥重要作用。

 DESCRIPTION (provided by applicant) Asthma is a chronic inflammatory airway disease currently affecting 1 in 12 adults in the United States. T helper (Th) cells are immune cells that orchestrate the lung inflammatory response in asthma through secretion of inflammatory cytokines and recruitment of other immune cells. While the Th2 subset of cells has been most commonly studied in asthma, Th17 cells have also been implicated in disease pathogenesis in at least some subtypes of asthma. Th17 cells mediate anti-bacterial and anti-fungal immunity and they are clearly associated with autoimmune diseases, but their precise role in the pathogenesis of asthma remains poorly understood. The proposed work aims to elucidate the regulation of Th17 cells by microRNAs (miRNAs) to gain a better appreciation of their dysregulation in diseases such as asthma. miRNAs have emerged as important regulators of many aspects of immune cell differentiation and function. The cell fate decisions of activated T helper cells are particularly sensitive to precise dosing of regulatory factors, and are therefore subject to regulation by the fine-tuning activity of miRNAs. Recent work has shown that the miR-17~92 cluster restrains the expression of subset-inappropriate genes in T follicular helper (TFH) cells. In contrast, how miR-17~92 regulates the differentiation and function of Th17 cells remains unknown. The major goal of this work is to define the role of the miR-17~92 cluster in Th17 cell differentiation in vitro and its potential functional significance in asthma using airway inflammation models. Aim 1 will combine the use of miR-17~92 conditional knockout mice and manipulation of individual miRNAs within the cluster to clarify the role of these miRNAs in regulating Th17 cell differentiation in vitro and by the examination of Th17 resident tissues in vivo. Preliminary data suggests that miR-17~92 inhibits Th17 cell differentiation, which is opposite to its effects in Th1, Th2, and TFH cells. Aim 2 will assess the mechanisms by which miR-17~92 cluster miRNAs target gene expression networks that control Th17 cell biology. Finally, Aim 3 will determine the impact of miRNA regulation of Th17 cells in asthma using airway inflammation models. This work will provide valuable insights into the molecular events that govern Th cell fate decisions and plasticity and its impact in a common chronic inflammatory disease. Additionally, this work may help identify more specific treatments and improve outcomes for patients with sub-phenotypes of asthma where Th17 cells play a significant role in the inflammatory response.