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

• 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
• 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

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)：定义一种新的MS易感基因IL7R阿尔法链的功能作用。多发性硬化症(MS)是一种中枢神经系统(CNS)衰弱的神经退行性疾病，被认为是由T细胞自身免疫介导的，导致神经系统炎症和进行性神经功能障碍。多发性硬化症的“复杂疾病”性质使人们很难识别与该病有关的基因，也很难理解该病的潜在分子机制。我们最近产生了令人兴奋的新数据，发现与白介素7α链受体基因(IL7R1)内的SNP的多发性硬化症显著相关。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，导致IL7R1可溶性形式的产生增加。这笔赠款的目标是在这一开创性发现的基础上再接再厉。我们建议确定参与外显子6 IL-7R1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)和胸腺基质淋巴生成素(TSLP)通路的影响，以及这对NAOVE T细胞分化和记忆性T细胞动态平衡的影响。通过阐明这些机制，我们希望能更好地了解IL7R1在MS的发病机制中的作用。 公共卫生相关性：多发性硬化症(MS)是一种衰弱的中枢神经系统退行性疾病，在美国影响着40多万人。我们最近产生了令人兴奋的新数据，其中确定了与MS有关的一个基因(IL-7R)。这项资助建立在我们发现的基础上，通过调查候选基因在免疫反应中发挥的功能以及这可能如何有助于MS。我们建议比较MS患者和对照组特定免疫细胞中IL-7R的功能，以确定IL-7R如何影响免疫细胞的维持。