Next generation systems analysis of pathogenetic mechanisms underlying CNS autoimmunity

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。这种疾病是由免疫调节对中枢神经系统的异常攻击引起的， 这会导致组织破坏和随后的神经功能障碍。病程差异很大， 个体到个体，从复发-缓解型多发性硬化症到初发进展型多发性硬化症，多发性硬化症的发病率是 在女性中很常见，但在男性中往往更严重。多发性硬化症具有重要的可遗传成分， 30%的疾病风险是由基因决定的。虽然最近的研究已经确定了候选基因 目前尚不清楚这些基因是如何发挥作用的，以及这些基因是否真的存在 有因果关系的。此外，目前还不清楚为什么有些人会患上不同形式的这种疾病，以及为什么会有 男性和女性之间的差异。这类问题即使不是不可能解决，也是非常困难的。 在对人类的研究中。在本应用程序中，我们建议使用MS的鼠标模型来解决这个问题。 小鼠模型提供了强大的遗传工具，并允许进行因果机制研究。我们将用一本小说 老鼠遗传模型，旨在更好地代表人类种群的复杂遗传结构， 这将使我们能够剖析MS发病机制下的复杂遗传结构，并识别 导致这种疾病的各种鲜为人知的方面的特定基因。

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.