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：
8505038
负责人：
SIMON G GREGORY
金额：
$ 34.02万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505038
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 exon skipping 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.

描述（由申请人提供）：定义新型 MS 易感基因 IL7R α 链的功能作用。多发性硬化症 (MS) 是一种使人衰弱的中枢神经系统 (CNS) 神经退行性疾病，被认为是由 T 细胞自身免疫介导的，会导致神经炎症和进行性神经功能障碍。多发性硬化症的“复杂疾病”性质使得识别与该疾病有关的基因和理解该疾病的潜在分子机制变得困难。我们最近生成了令人兴奋的新数据，该数据已确定白细胞介素 7 α 链受体基因 (IL7R1) 内的 SNP 与 MS 显着相关。此外，我们已经证明相关的 SNP 会导致蛋白质跨膜结构域的跳跃增加，从而导致可溶形式 IL7R1 的产生增加。这笔赠款的目的是在这一突破性发现的基础上再接再厉。我们建议鉴定参与外显子 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) 和胸腺基质淋巴细胞生成素 (TSLP) 途径的影响，以及这对外显子跳跃的影响。幼稚 T 细胞分化和记忆 T 细胞稳态。通过阐明这些机制，我们希望更好地了解 IL7R1 在功能上与 MS 病因学有关。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

DOI：
10.1016/j.cell.2017.03.007
发表时间：
2017-03-23
期刊：
Cell
影响因子：
64.5
作者：
Galarza-Muñoz G;Briggs FBS;Evsyukova I;Schott-Lerner G;Kennedy EM;Nyanhete T;Wang L;Bergamaschi L;Widen SG;Tomaras GD;Ko DC;Bradrick SS;Barcellos LF;Gregory SG;Garcia-Blanco MA
通讯作者：
Garcia-Blanco MA