STAT1: New regulator of inflammatory Th17 and Th2 cells

 描述（由申请人提供）：过敏性疾病的标志是Th 2和Th 17细胞在炎症部位的浸润和积聚。因此，今天越来越清楚的是，需要了解致病性Th 2和Th 17细胞的生物学以及操纵它们的功能以治疗过敏性气道炎症的方法，并且一种创新且合理的方法是鉴定Th 2和Th 17细胞中对其功能不可或缺并且在治疗上可接近的共同靶标。致病性T辅助细胞亚群的产生依赖于细胞因子刺激和随后的信号转导和转录激活因子（STAT）蛋白的激活。近年来，研究表明转录因子STAT 1促进过敏原诱导的气道炎症，但STAT 1在哮喘发病机制中的确切作用尚未得到解决。我们的初步数据表明，STAT 1是必需的表达的Th 2和Th 17的签名细胞因子和转录因子，表明STAT 1的关键作用，在Th 2和Th 17细胞的发展，从而在哮喘发病机制。事实上，STAT 1缺陷小鼠表现出哮喘发展减少。重要的是，我们已经开发了一种基于肽的STAT 1抑制剂，其靶向小鼠和人T细胞中的STAT 1活性。一个剂量的抑制剂给药显著减少了Th 2和Th 17衍生的细胞因子的表达，表明其未来的治疗应用。基于这些发现，我们假设STAT 1靶向将有助于破坏致病性Th 2和Th 17细胞反应，从而减轻哮喘症状。在目标1中，我们提出了确定细胞和分子机制，使STAT 1调节Th 2和Th 17细胞分化和可塑性，这些子集之间利用基因敲低的方法。我们还将采用独特的IL-4-GFP和IL-17-RFP报告小鼠模型来定义STAT 1在正常和自身免疫环境中的Th 2，Th 17和Th 2/Th 17细胞编程中的功能。在Aim 2中，我们将阐明通过给予STAT 1抑制剂靶向促变应性Th 2和Th 17细胞中的STAT 1功能是否是预防和治疗变应性哮喘的重要检查点。这项研究将为表征STAT 1在Th 2和Th 17细胞中功能的分子机制提供新的重要见解，可能将STAT 1作为治疗或预防患者过敏性哮喘的新分子靶点。

 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.