Next generation systems analysis of pathogenetic mechanisms underlying CNS autoimmunity

中枢神经系统自身免疫发病机制的下一代系统分析

• 批准号: 9768066
• 负责人: Dimitry N Krementsov
• 金额: $ 27.3万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-25 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768066
• 关键词: Address; Alleles; Animal Model; Architecture; Autoimmune Diseases; Autoimmune Process; Axon; CNS autoimmunity; Candidate Disease Gene; Cells; Central Nervous System Diseases; Chromosomes; Chronic; Chronic Disease; Clinical; Complex; Computational algorithm; Congenic Strain; Consomic Strain; Data; Data Set; Demyelinations; Deterioration; Disease; Disease Progression; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Genetics; Female; Genes; Genetic; Genetic Models; Genetic Recombination; Genetic Risk; Genetic Structures; Genetic Variation; Genome; Gliosis; Heritability; Heterogeneity; Human; Immune; Incidence; Individual; Infiltration; Inflammatory; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Network-based; Neuraxis; Neurologic; Neurologic Dysfunctions; Pathogenesis; Pathology; Phenotype; Population; Predisposition; Primary Progressive Multiple Sclerosis; Publishing; Relapse; Relapsing-Remitting Multiple Sclerosis; Resolution; Risk; Role; SJL/J Mouse; Severities; Sex Differences; Susceptibility Gene; System; Systems Analysis; Technology; Time; Tissues; Woman; Work; analytical tool; axon injury; causal variant; chronic autoimmune disease; cohort; consomic; design; disability; disorder risk; experimental study; forward genetics; genetic analysis; genetic approach; genetic architecture; genetic association; genetic resource; genetic variant; genome wide association study; genome-wide; genomic data; insight; knockout gene; male; men; mouse model; next generation; novel; outcome forecast; reverse genetics; success; tool; young adult

Project Abstract/Summary Multiple sclerosis (MS) is a chronic disease that is the leading cause of non-traumatic neurological disability in young adults. The disease is caused by an aberrant immune-mediated attack on the central nervous system, which causes tissue destruction and subsequent neurologic disability. Disease course varies greatly from individual to individual, from relapsing-remitting MS, to primary progressive MS. MS is three times more common in women, but tends to be more severe in men. MS has a significant heritable component, with up to 30% of the disease risk being genetically determined. While recent studies have identified candidate genes that are associated with MS risk, it remains unclear how these genes work and whether these are truly causative. Additionally, it is unclear why some individuals get different forms of this disease, and why there are differences between men and women. These types of questions are very difficult, if not impossible, to address in studies in humans. In this application, we propose to use a mouse model of MS to address this question. Mouse models offer powerful genetic tools, and allow for cause/effect mechanistic studies. We will use a novel mouse genetic model that is designed to better represent the complex genetic structure of human populations, which will allow us to dissect the complex genetic architecture underlying MS pathogenesis, and to identify specific genes responsible for various poorly understood aspects of this disease.

项目摘要/摘要 多发性硬化症（MS）是一种慢性疾病，是非创伤性神经功能障碍的主要原因， 年轻人这种疾病是由中枢神经系统的异常免疫介导的攻击引起的， 这会导致组织破坏和随后的神经功能障碍。病程变化很大， 从个体到个体，从复发缓解型MS到原发性进行性MS。MS是 常见于女性，但在男性中往往更严重。MS具有显著的遗传成分， 30%的疾病风险由基因决定。虽然最近的研究已经确定了候选基因 与MS风险相关的基因，目前尚不清楚这些基因是如何工作的，以及这些基因是否真的与MS风险相关。 使役的此外，目前还不清楚为什么有些人得到不同形式的这种疾病，以及为什么有 男女之间的差异。这些类型的问题是非常困难的，如果不是不可能的，以解决 在人类的研究中。在本申请中，我们建议使用MS的小鼠模型来解决这个问题。 小鼠模型提供了强大的遗传工具，并允许因果机制研究。我们会用一本小说 小鼠遗传模型旨在更好地代表人类群体的复杂遗传结构， 这将使我们能够剖析MS发病机制下复杂的遗传结构，并确定 对这种疾病的各个方面知之甚少的特定基因。