STAT4 regulation of effector CD4 T cells and CNS inflammation

STAT4对效应CD4 T细胞和中枢神经系统炎症的调节

• 批准号: 8885328
• 负责人: Laurie Ellen Harrington
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885328
• 关键词: Apoptosis; Autoimmune Process; CD4 Positive T Lymphocytes; Cell Survival; Cells; Characteristics; Chronic; Complex; Coupled; Data; Demyelinating Diseases; Development; Disease; Disease susceptibility; Employee Strikes; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Future; Gene Activation; Generations; Genes; Genetic Predisposition to Disease; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Individual; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Laboratories; Lead; Learning; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Multiple Sclerosis; Neuraxis; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Predisposition; Process; Production; Property; Publishing; Regulation; Reporting; Research Design; Role; STAT3 gene; STAT4 gene; Shapes; Signal Transduction; Susceptibility Gene; T-Cell Proliferation; Testing; Therapeutic Intervention; United States; cell motility; central nervous system demyelinating disorder; cytokine; genetic variant; genome wide association study; interleukin-23; mouse model; novel; prevent; public health relevance; receptor; receptor expression; risk variant; transcription factor

 DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that afflicts over two million individuals worldwide. While the etiology of MS remains unknown, it is clear that there is a genetic predisposition for the disease. Genome-wide association studies indicate a correlation between genetic variants of numerous inflammatory genes and disease susceptibility. Most recently, a susceptibility variant within the intronic sequence of the STAT4 gene was identified. Importantly, expression of the transcription factor STAT4 is essential for the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These data signify a potentially integral role for STAT4 during the pathogenesis of MS. Currently, the mechanism by which STAT4 mediates CNS inflammation remains elusive; however our own preliminary data show that CD4 T cell intrinsic expression of STAT4 is vital for EAE. Additionally, striking data from our laboratory demonstrates that STAT4 is required for accumulation of CD4 T cells in the inflamed CNS, as well as for the full array of CD4 T cell effector functions. Interestingly, CD4 T cells lacking expression of the IL-23 receptor complex exhibit many of the same characteristics of STAT4 deficient CD4 T cells, and the earliest reports published on IL-23 documented that it induced the phosphorylation of not only STAT3, but also STAT4. STAT4 is also known to regulate expression of IL-12Rß1, one component of the IL-23 receptor complex. Together, the published findings and our preliminary data lead us to hypothesize that IL-23 and STAT4 function in the same pathway in CD4 T cells during EAE, and that STAT4 governs the pathogenic signature in CD4 T cells necessary to confer encephalogenicity during CNS inflammation. To test this, we propose the following specific aims: Aim 1: To determine the impact of STAT4 expression on CD4 T cell functionality during CNS inflammation. Aim 2: To determine the prerequisite of intrinsic STAT4 expression for CD4 T cell accumulation during CNS inflammation. Aim 3: To determine the interplay between STAT4 signaling and the IL-23 pathway in CD4 T cells during CNS inflammation. Collectively, these studies are designed to provide new information regarding the cellular mediators of CNS inflammation during EAE and help to precisely define the properties and molecular regulators which control the development of encephalogenic CD4 T cells. Our long-term goal is elucidate the significance of STAT4 in promoting chronic inflammatory disorders, such as multiple sclerosis, in hopes that a transcriptional target will be identified which can be used for future therapeutic interventions.

 描述（由申请人提供）：多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）脱髓鞘疾病，在全球范围内困扰着超过200万人。虽然MS的病因仍然未知，但很明显，这种疾病存在遗传易感性。全基因组关联研究表明，许多炎症基因的遗传变异与疾病易感性之间存在相关性。最近，在STAT 4基因的内含子序列内鉴定出易感性变体。重要的是，转录因子STAT 4的表达是必不可少的实验性自身免疫性脑脊髓炎（EAE），MS的小鼠模型的发展。这些数据表明一个潜在的不可或缺的作用，STAT 4在MS的发病机制。目前，STAT 4介导中枢神经系统炎症的机制仍然难以捉摸，但我们自己的初步数据显示，CD 4 T细胞固有的STAT 4表达是EAE是至关重要的。此外，来自我们实验室的惊人数据表明，STAT 4是炎症CNS中CD 4 T细胞积累所必需的，也是CD 4 T细胞效应子功能的全部阵列所必需的。有趣的是，缺乏IL-23受体复合物表达的CD 4 T细胞表现出许多与STAT 4缺陷型CD 4 T细胞相同的特征，并且最早发表的关于IL-23的报告证明它不仅诱导STAT 3的磷酸化，而且诱导STAT 4的磷酸化。还已知STAT 4调节IL-23受体复合物的一种组分IL-12 R β 1的表达。总之，已发表的研究结果和我们的初步数据使我们假设IL-23和STAT 4在EAE期间在CD 4 T细胞中以相同的途径起作用，并且STAT 4控制在CNS炎症期间赋予致脑性所必需的CD 4 T细胞中的致病性特征。为了测试这一点，我们提出了以下具体目标：目标1：确定在CNS炎症过程中STAT 4表达对CD 4 T细胞功能的影响。 目的2：探讨中枢神经系统炎症过程中内源性STAT 4表达对CD 4 T细胞聚集的影响。 目的3：确定CNS炎症过程中CD 4 T细胞中STAT 4信号传导和IL-23通路之间的相互作用。总的来说，这些研究旨在提供关于EAE期间CNS炎症的细胞介质的新信息，并有助于精确定义控制脑源性CD 4 T细胞发育的特性和分子调节剂。我们的长期目标是阐明STAT 4在促进多发性硬化症等慢性炎症性疾病中的重要性，希望能够识别出可用于未来治疗干预的转录靶点。