MicroRNA regulation of Th17 cell differentiation

 描述(由申请人提供)哮喘是一种慢性炎症性呼吸道疾病，目前在美国每12个成年人中就有1个受到影响。辅助性T细胞(Th)是一种免疫细胞，通过分泌炎性细胞因子和募集其他免疫细胞来协调哮喘患者的肺部炎症反应。虽然Th2细胞亚群在哮喘中的研究最常见，但Th17细胞也与至少某些哮喘亚型的疾病发病机制有关。Th17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尚不清楚。这项拟议的工作旨在阐明microRNAs(MiRNAs)对Th17细胞的调节，以更好地了解它们在哮喘等疾病中的调节失调。MiRNAs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。激活的T辅助细胞的细胞命运决定对调控因子的精确剂量特别敏感，因此受到miRNAs微调活性的调节。最近的研究表明，miR-17~92簇抑制了T滤泡辅助者(TFH)细胞亚群不适当基因的表达。相比之下，miR-17~92如何调节Th17细胞的分化和功能尚不清楚。这项工作的主要目的是确定miR-17~92簇在体外Th17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结合使用miR-17~92条件基因敲除小鼠和对簇内单个miRNAs的操作，阐明这些miRNAs在体外调节Th17细胞分化中的作用，并通过体内Th17驻留组织的检查来阐明这些miRNAs在调节Th17细胞分化中的作用。初步数据表明，miR-17~92抑制Th17细胞分化，这与其对Th1、Th2和TFH细胞的作用相反。目的2将评估miR-17~92簇miRNAs靶向控制Th17细胞生物学的基因表达网络的机制。最后，Aim 3将利用呼吸道炎症模型确定miRNA对Th17细胞在哮喘中的调节作用。这项工作将为控制Th细胞命运决定和可塑性的分子事件及其在常见慢性炎症性疾病中的影响提供有价值的见解。此外，这项工作可能有助于确定更具体的治疗方法，并改善哮喘亚型患者的预后，其中Th17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.