Molecular Analysis of Genes Uniquely Expressed by Encephalitogenic T Cells

描述（由申请人提供）：MS的病因不明，无法治愈，目前的治疗方法疗效有限。我的实验室致力于鉴定致脑炎T细胞致病性的关键分子。由于中枢神经系统是一个免疫豁免的组织和免疫监视是有限的，我们假设，致脑炎性T细胞表达独特的分子，提高其致脑炎的能力，这些分子可能是治疗MS的目标。在实验性自身免疫性脑脊髓炎（EAE），MS，髓鞘特异性Th1和Th17的模型可以诱导疾病。然而，我们也知道并非所有髓鞘特异性Th1和Th17细胞都诱导疾病，这表明髓鞘特异性T细胞表达促炎细胞因子不足以认为髓鞘特异性T细胞是致脑炎的。在所提出的研究中，我们将鉴定区分致脑炎和非致脑炎髓鞘特异性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：鉴定在致脑炎和致脑炎较少的髓鞘特异性Th1细胞中差异表达的分子，其有助于T细胞致病性。具体目标二：鉴定致脑炎和非致脑炎髓鞘特异性Th17细胞中差异表达的分子，这些分子有助于T细胞致病性。对疾病关键分子的鉴定主要通过基因敲除研究完成。然而，这些研究提供了关于该分子在疾病中的作用的有限信息，并且许多敲除研究已经产生了令人惊讶的表型。利用非常特异和密切相关的T细胞群中的差异表达，我们应该能够鉴定出几种与致脑炎性明显相关的分子，并确定对这一过程至关重要的分子途径。这些分子将为MS新治疗剂的开发提供靶点。 公共卫生相关性：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MS的原因尚不清楚，因此无法治愈，目前的治疗方法仅部分有效。大约有35万美国人患有多发性硬化症，许多人在一生中将成为身体残疾人。目前的研究重点是识别破坏髓鞘的免疫细胞的独特性，以便为MS和其他免疫介导的疾病开发新的治疗药物。

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.