Defining the Functional Role of a Novel MS Susceptibility Gene, IL7R alpha chain

描述（由申请人提供）：定义新型MS易感基因IL 7 R α链的功能作用。多发性硬化（MS）是中枢神经系统（CNS）的衰弱性神经退行性疾病，其被认为是由T细胞自身免疫介导的，并引起神经炎症和进行性神经功能障碍。MS的“复杂疾病”性质使得难以鉴定与疾病有关的基因，并理解疾病的潜在分子机制。我们最近产生了令人兴奋的新数据，这些数据已经确定了白细胞介素7 α链受体基因（IL 7 R1）内的SNP与MS的显著关联。此外，我们已经证明，相关的SNP导致蛋白质跨膜结构域的跳跃增加，导致可溶形式的IL 7 R1的产生增加。这项资助的目的是在这一开创性发现的基础上再接再厉。我们拟鉴定参与外显子6 IL-7 R1剪接的顺式和反式因子，确定外显子跳跃对白细胞介素7（IL-7）和胸腺基质淋巴细胞生成素（TSLP）通路的影响，以及这对原始T细胞分化和记忆T细胞稳态的影响。通过阐明这些机制，我们希望能够更好地了解IL 7 R1在MS病因学中的作用。 公共卫生相关性：多发性硬化症（MS）是一种中枢神经系统的衰弱性神经退行性疾病，在美国影响超过40万人。我们最近产生了令人兴奋的新数据，其中已经确定了一个基因（IL-7 R）牵连在MS。这个补助金建立在我们的发现，通过调查的功能，候选基因在免疫反应中发挥作用，这可能有助于MS。我们建议比较IL-7 R在MS患者和控制个人的特定免疫细胞的功能，以确定IL-7 R如何影响免疫细胞的维护。

DESCRIPTION (provided by applicant): Defining the functional role of a novel MS susceptibility gene, IL7R alpha chain. Multiple sclerosis (MS) is a debilitating neurodegenerative disorder of the central nervous system (CNS) that is thought to be mediated by T-cell autoimmunity and causes neurological inflammation and progressive neurological dysfunction. The `complex disease' nature of MS has made it difficult to identify genes implicated in, and understand the underlying molecular mechanisms of the disease. We have recently generated exciting new data which has identified significant association with MS of a SNP within the interleukin 7 alpha chain receptor gene (IL7R1). Further, we have proven that the associated SNP leads to increased skipping of the transmembrane domain of the protein, resulting in increased production of the soluble form of IL7R1. The objective of this grant is to build upon this ground breaking discovery. We propose to identify the cis- and trans- factors involved in exon 6 IL-7R1 splicing, determine the effect that exon skipping has upon interleukin 7 (IL-7) and thymic stromal lymphopoietin (TSLP) pathways, and the influences that this has upon naove T- cell differentiation and memory T-cell homeostasis. By elucidating these mechanisms we hope to gain a better understand IL7R1 is functionally implicated in the etiology of MS. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a debilitating neurodegenerative disorder of the central nervous system that affects more than 400,000 individuals in the United States. We have recently generated exciting new data in which have identified a gene (IL-7R) implicated in MS. This grant builds upon our discovery by investigating of the functional that the candidate gene plays in immune response and how this may contribute to MS. We propose to compare the function of IL-7R in specific immune cells in MS patients and control individuals to identify how IL-7R influences immune cell maintenance.