STAT1: New regulator of inflammatory Th17 and Th2 cells

STAT1：炎症 Th17 和 Th2 细胞的新调节因子

• 批准号: 9112386
• 负责人: Roza Insafetdinovna Nurieva
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112386
• 关键词: Address; Allergens; Allergic; Allergic Disease; Allergic inflammation; Asthma; Autoimmune Process; Automobile Driving; Biological Models; Biology; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Data; Development; Disease; Dose; Exhibits; Experimental Models; Extrinsic asthma; Future; Gene Expression; Generations; Genes; Helper-Inducer T-Lymphocyte; Human; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukin-4; Investigation; Knockout Mice; Knowledge; Lead; Lung diseases; Methods; Molecular; Mus; Oryza; Pathogenesis; Patients; Peptide Hydrolases; Peptides; Play; Prevention; Property; Proteins; Reagent; Regulation; Reporter; Research; Role; STAT protein; STAT1 gene; Signal Transduction; Site; Staging; Symptoms; T-Lymphocyte; Th2 Cells; Therapeutic; Time; Tissues; Work; airway inflammation; allergic airway inflammation; base; cytokine; in vivo; inhibitor/antagonist; innovation; insight; knock-down; molecular targeted therapies; mouse model; novel; prevent; programs; public health relevance; research study; response; tool; transcription factor

 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.

 描述（由适用提供）：过敏性疾病的标志是在炎症部位浸润Th2和Th17细胞的浸润和积累。这就是说，今天很清楚，需要了解致病性TH2和TH17细胞的生物学以及需要操纵其功能以治疗过敏性气道感染的方法，而一种创新和合理的方法是识别Th2和Th17细胞中具有可用于其功能和史无前例的及其可及的TH2和TH17细胞中的共同靶标。致病性T辅助子群的产生依赖于细胞因子刺激以及随后的信号传感器和转录激活因子（STAT）蛋白的激活。最近，有人提出转录因子STAT1促进过敏原诱导的气道注射。但是，尚未解决STAT1在哮喘发病机理中的精确作用。我们的初步数据表明，STAT1表达Th2和Th17签名细胞因子和转录因子需要STAT1，这表明STAT1在Th2和Th17细胞发育中的关键作用，因此在哮喘发病机理中表现出了关键作用。实际上，STAT1缺陷小鼠暴露了哮喘的发育。重要的是，我们开发了一种基于肽的STAT1抑制剂，该抑制剂靶向小鼠和人T细胞中的STAT1活性。抑制剂给药的一剂显着降低了Th2和Th17衍生的细胞因子的表达，表明其未来的治疗应用。根据这些发现，我们假设STAT1靶向将有助于破坏致病性TH2和TH17细胞反应，从而减少哮喘症状。在AIM 1中，我们建议通过利用基因敲低方法来确定STAT1在这些子集中调节Th2和Th17细胞分化和可塑性的细胞和分子机制。我们还将采用唯一的IL-4-GFP和IL-17-RFP记者鼠标模型来定义在正常和自动免疫设置中TH2，TH17和TH2/TH2/TH17细胞编程中STAT1的功能。在AIM2中，我们将阐明通过施用STAT1抑制剂来靶向验证抗性TH2和Th17细胞中的靶向是否是预防和治疗过敏性哮喘的必不可少的检查点。拟议的研究将为Th2和Th17细胞中STAT1功能基础机制的表征的表征提供新的重要洞察力，这可能可能将STAT1作为治疗或预防患者治疗或预防过敏性哮喘的新分子靶标。