Molecular Analysis of Genes Uniquely Expressed by Encephalitogenic T Cells

描述（由申请人提供）：MS的病因不明，没有治愈方法，目前的治疗方法疗效有限。我的实验室专注于鉴定对致脑性T细胞致病性至关重要的分子。由于中枢神经系统是一种免疫特权组织，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，增强其脑源性能力，这些分子可能是MS的治疗靶点。在实验性自身免疫性脑脊髓炎（EAE）中，MS模型，髓磷脂特异性Th1和Th17可以诱导疾病。然而，我们也知道并非所有髓磷脂特异性Th1和Th17细胞都会诱导疾病，这表明髓磷脂特异性T细胞表达促炎细胞因子不足以认为髓磷脂特异性T细胞是脑源性的。在本研究中，我们将鉴定区分脑源性和非脑源性髓磷脂特异性Th1和Th17细胞的分子，并分析这些分子在EAE和ms中的作用。具体目的1：鉴定在脑源性和非脑源性髓磷脂特异性Th1细胞中差异表达的有助于T细胞致病性的分子。特异性目标2：鉴定在脑源性和非脑源性髓磷脂特异性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是通过基因敲除研究完成的。然而，这些研究对该分子在疾病中的作用提供了有限的信息，许多敲除研究产生了令人惊讶的表型。通过在非常特殊和密切相关的T细胞群体中使用差异表达，我们应该能够识别出几个与脑致生性明显相关的分子，并确定对这一过程至关重要的分子途径。这些分子将为开发新的多发性硬化症治疗剂提供靶点。

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.