Molecular Analysis of Genes Uniquely Expressed by Encephalitogenic T Cells

描述(申请人提供)：多发性硬化症的病因不明，目前还没有治愈的方法，目前的治疗方法疗效有限。我的实验室专注于识别对脑源性T细胞致病至关重要的分子。由于中枢神经系统是一种免疫优势组织，免疫监测是有限的，我们假设脑源性T细胞表达独特的分子来增强其脑源性能力，这些分子可能是实验性自身免疫性脑脊髓炎(EAE)的治疗靶点，EAE是一种MS模型，髓鞘特异性Th1和Th17可以诱发疾病。然而，我们也知道并不是所有髓鞘特异的Th1和Th17细胞都会导致疾病，这表明髓鞘特异的T细胞表达促炎细胞因子并不足以认为髓鞘特异的T细胞是脑源性的。在这项拟议的研究中，我们将识别区分脑源性和非脑源性髓鞘特异性Th1和Th17细胞的分子，并分析这些分子在EAE和MS中的作用。具体目标1：识别在脑源性和非脑源性髓鞘特异性Th1细胞中差异表达的分子，这些分子有助于T细胞的致病作用。具体目标2：确定在脑源性和非脑源性髓鞘特异性Th17细胞中差异表达的分子，这些分子有助于T细胞的致病作用。对疾病关键分子的鉴定在很大程度上是通过基因敲除研究完成的。然而，这些研究提供的关于该分子在疾病中的作用的信息有限，许多基因敲除研究产生了令人惊讶的表型。利用在非常特定和密切相关的T细胞群体中的差异表达，我们应该能够识别几个明显与脑发生相关的分子，并确定对这一过程至关重要的分子途径。这些分子将为开发新的多发性硬化症治疗药物提供靶点。 公共卫生相关性：项目叙述多发性硬化症(MS)是一种免疫介导的疾病，破坏轴突周围的髓鞘，导致神经传导受损和功能丧失。由于多发性硬化症的病因尚不清楚，目前还没有治愈的方法，目前的治疗方法只能起到部分作用。大约有35万美国人患有多发性硬化症，其中许多人将在有生之年成为身体残疾。目前的研究集中在识别破坏髓鞘的免疫细胞的独特性，以便开发新的治疗多发性硬化症和其他免疫介导性疾病的药物。

DESCRIPTION (provided by applicant): The cause of MS is unknown, there is no cure, and the current therapies have limited efficacy. My laboratory focuses on identifying molecules critical to the pathogenicity of encephalitogenic T cells. Since the CNS is an immune-privileged tissue and immunological surveillance is limited, we hypothesize that encephalitogenic T cells express unique molecules that enhance their encephalitogenic capacity and that these molecules may be therapeutic targets for MS. In experimental autoimmune encephalomyelitis (EAE), a model of MS, myelin-specific Th1 and Th17 can induce disease. However, we also know that not all myelin-specific Th1 and Th17 cells induce disease, suggesting that expression of pro-inflammatory cytokines by myelin-specific T cells is not sufficient to deem a myelin-specific T cell encephalitogenic. In the proposed study, we will identify molecules that distinguish encephalitogenic and non- encephalitogenic myelin-specific Th1 and Th17 cells and analyze the role of these molecules in EAE and MS. Specific Aim 1: Identify molecules differentially expressed in encephalitogenic and less-encephalitogenic myelin-specific Th1 cells that contribute to T cell pathogenicity. Specific Aim 2: Identify molecules differentially expressed in encephalitogenic and non-encephalitogenic myelin- specific Th17 cells that contribute to T cell pathogenicity. Identification of molecules critical for disease has largely been done by gene knockout studies. However, these studies give limited information on the role of the molecule in disease and many knockout studies have yielded surprising phenotypes. Using differential expression in very specific and closely related T cell populations, we should be able to identify several molecules that are clearly associated with encephalitogenicity and determine molecular pathways that are critical for this process. These molecules would provide targets for the development of new therapeutic agents for MS. PUBLIC HEALTH RELEVANCE: Project Narrative Multiple Sclerosis (MS) is an immune-mediated disease that destroys the myelin sheath around axons, resulting in impaired nerve conduction and functional loss. Since the cause of MS is unknown, there is no cure, and current therapies are only partially affective. Approximately 350,000 Americans live with MS and many will become physically handicapped during their lifetime. The current study focuses on identifying unique to the immune cells that damage the myelin, so that new therapeutic agents can be developed for MS and other immune-mediated diseases.