STAT1: New regulator of inflammatory Th17 and Th2 cells

 描述(申请人提供)：过敏性疾病的标志是炎症部位的Th2和Th17细胞的渗透和积聚。因此，今天变得越来越清楚，需要了解致病的Th2和Th17细胞的生物学特性以及如何操纵它们的功能来治疗过敏性呼吸道炎症，一个创新和合理的方法是确定Th2和Th17细胞中的共同靶点(S)，这些靶点对它们的功能是必不可少的，也是治疗上可以获得的。致病T辅助细胞亚群的产生依赖于细胞因子的刺激以及随后信号转导和转录激活因子(STAT)蛋白的激活。最近，转录因子STAT1被认为促进变应原诱导的呼吸道炎症，然而，STAT1在哮喘发病机制中的确切作用尚未被阐明。我们的初步数据表明，STAT1是Th2和Th17标志性细胞因子和转录因子表达所必需的，这表明STAT1在Th2和Th17细胞发育中发挥关键作用，从而在哮喘发病机制中发挥关键作用。事实上，STAT1基因缺陷的小鼠表现出哮喘发展的减少。重要的是，我们已经开发了一种基于多肽的STAT1抑制剂，它针对小鼠和人类T细胞中的STAT1活性。一次给药可显著降低Th2和Th17来源的细胞因子的表达，预示着其未来的治疗应用。基于这些发现，我们假设STAT1靶向将有助于破坏致病的Th2和Th17细胞反应，从而减少哮喘症状。在目标1中，我们建议利用基因敲除方法来确定STAT1调节Th2和Th17细胞分化和这些亚群之间可塑性的细胞和分子机制。我们还将使用独特的IL-4-GFP和IL-17-RFP报告小鼠模型来确定STAT1在正常和自身免疫设置下的Th2、Th17和Th2/Th17细胞编程中的功能。在AIM2中，我们将阐明通过给予STAT1抑制剂来靶向致敏的Th2和Th17细胞中的STAT1功能是否是预防和治疗过敏性哮喘的重要关卡。这项拟议的研究将为表征Th2和Th17细胞中STAT1功能的分子机制提供新的重要见解，可能会使STAT1成为治疗或预防患者过敏性哮喘的新的分子靶点。

 DESCRIPTION (provided by applicant): The hallmark of allergic diseases is the infiltration and accumulation of Th2 and Th17 cells at the sites of inflammation. Thus, today it is becoming clear that understanding the biology of pathogenic Th2 and Th17 cells and ways to manipulate their function for the treatment of allergic airway inflammation are needed, and one innovative and rational approach is to identify common target(s) in Th2 and Th17 cells that are indispensable for their function and also therapeutically accessible. The generation of pathogenic T helper subsets relies upon cytokine stimulation and the subsequent activation of Signal Transducer and Activator of Transcription (STAT) proteins. Recently, it was suggested that the transcription factor STAT1 promotes allergen-induced airway inflammation; however the precise role of STAT1 in asthma pathogenesis has not been addressed yet. Our preliminary data indicates that STAT1 is required for expression of Th2 and Th17 signature cytokines and transcriptional factors, suggesting the pivotal role of STAT1 in Th2 and Th17 cell development and consequently in asthma pathogenesis. In fact, STAT1-deficient mice exhibited reduced asthma development. Importantly, we have developed a peptide-based STAT1 inhibitor which targets STAT1 activity in both mouse and human T cells. One dose of the inhibitor administration significantly diminished the expression of Th2 and Th17-derived cytokines, indicating its future therapeutic applications. Based on these findings, we hypothesize that STAT1 targeting will help to disrupt the pathogenic Th2 and Th17 cell responses and consequently decrease asthma symptoms. In Aim 1, we propose to determine the cellular and molecular mechanisms whereby STAT1 regulates Th2 and Th17 cell differentiation and plasticity among these subsets by utilizing gene knockdown approaches. We will also employ unique IL-4-GFP and IL-17-RFP reporter mouse models to define the function of STAT1 in Th2, Th17 and Th2/Th17 cell programming in both normal and autoimmune settings. In Aim2, we will elucidate whether targeting of STAT1 function in proallergic Th2 and Th17 cells by administering STAT1 inhibitors is an essential checkpoint for the prevention and treatment of allergic asthma. The proposed research will provide new significant insight into characterization of molecular mechanisms underlying STAT1 function in Th2 and Th17 cells that may potentially project STAT1 as a novel molecular target for the treatment or prevention of allergic asthma in the patients.