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

定义新型 MS 易感基因 IL7R α 链的功能作用

基本信息

批准号：
8092551
负责人：
SIMON G GREGORY
金额：
$ 32.52万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092551
关键词：
6p21.3 Affect Alleles Alternative Splicing Architecture Autoimmunity Binding Biological CD8B1 gene Candidate Disease Gene Cell Maintenance Cell Proliferation Cell Survival Cell physiology Cells Chromosomes Chronic Cognition Complex Copy Number Polymorphism Data Dependency Development Diagnosis Disease Disease susceptibility Etiology Exons Family Fatigue Gene Expression Genes Genetic Grant Histocompatibility Homeostasis IL7R gene Immune Immune response In Vitro Individual Inflammation Inflammatory Interleukin-7 Light Maintenance Mediating Membrane Memory Minor Molecular Molecular Analysis Multiple Sclerosis Muscle Weakness Myelin Nature Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Pathology Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Play Population Predisposition Process Production Protein Isoforms Proteins RNA Splicing Receptor Gene Relapsing-Remitting Multiple Sclerosis Repression Research Rest Risk Role SNP genotyping Sensory Signal Pathway Signal Transduction Susceptibility Gene T cell differentiation T cell regulation T memory cell T-Lymphocyte Testing Trans-Activators Trans-Splicing Transcriptional Silencer Elements Transmembrane Domain United States Wheelchairs alpha chain interleukin-7 receptor base case control cohort cytotoxic disability experience genetic analysis genetic association genetic linkage analysis human TSLP protein in vivo mRNA Expression novel outcome forecast pathogen protein expression public health relevance receptor binding response

项目摘要

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.

描述（由申请人提供）：定义新型MS敏感性基因IL7R alpha链的功能作用。多发性硬化症（MS）是中枢神经系统（CNS）的一种使人衰弱的神经退行性疾病，被认为是由T细胞自身免疫性介导的，并引起神经系统炎症和进行性神经功能障碍。 MS的“复杂疾病”的性质使得很难识别涉及与该疾病的潜在分子机制有关的基因。我们最近产生了令人兴奋的新数据，该数据已经确定了白介素7α链受体基因（IL7R1）中SNP的MS显着关联。此外，我们已经证明，相关的SNP导致蛋白质跨膜结构域的跳过增加，从而导致IL7R1的可溶性形式的产生增加。这笔赠款的目的是建立在这一基础上的发现。我们建议确定外显子6 IL-7R1剪接中涉及的顺式和转染因子，确定外显子跳过对介体7（IL-7）和胸腺基质淋巴细胞素（TSLP）途径的影响，以及该途径对NAOVE T-细胞分化和内存T-Cell Tcell issotstassis的影响。通过阐明这些机制，我们希望获得更好的理解IL7R1在功能上与MS的病因有关。公共卫生相关性：多发性硬化症（MS）是中枢神经系统的一种使人衰弱的神经退行性疾病，影响了美国超过40万人。我们最近生成了令人兴奋的新数据，其中已经确定了与MS有关的基因（IL-7R）。这项赠款是基于我们发现的基于我们发现的候选基因在免疫反应中发挥的功能以及这可能对MS有效的作用的基础。我们建议比较MS患者在特定免疫细胞中IL-7R的功能，并控制个体，以确定IL-7R如何影响免疫细胞维持。