Novel mouse models to dissect the role of genetics, sex, and environment in heterogeneous outcomes in CNS autoimmune disease

项目摘要/总结 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， 个体到个体，从复发缓解型MS到原发性进行性MS，后者高度衰弱， 难治的多发性硬化症在女性中的发病率是男性的三倍，但在男性中往往更为严重。MS具有 这是一个重要的遗传因素，高达30%的疾病风险是由基因决定的。虽然最近 研究已经确定了与MS风险相关的候选基因，但仍不清楚这些基因如何与MS风险相关。 工作，以及这些是否真的是因果关系。此外，完全不知道为什么有些人会 这种疾病的不同形式，以及为什么男女之间存在差异。其余70% 疾病风险来自环境或基因与环境的相互作用，这是一个有吸引力的途径 用于展示。然而，风险因素，特别是慢性γ疱疹病毒感染， 影响MS风险或进展尚不清楚。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，以及在本申请中，我们建议使用MS的动物模型。 强大的遗传工具，并允许因果机制的研究，但传统的小鼠模型是高度 缺乏遗传多样性。我们将使用几种新的小鼠遗传模型，旨在更好地 代表了人类群体复杂的遗传结构，这将使我们能够剖析复杂的遗传结构。 MS发病机制的基础架构，以确定负责各种鲜为人知的特定基因， 这种疾病的各个方面，并确定基因与环境的相互作用和新的机制， 环境风险因素。

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, the latter highly debilitating and refractory to treatment. 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 completely unknown why some individuals get different forms of this disease, and why there are differences between men and women. The other 70% of disease risk comes from environment or gene-by-environment interactions, representing an attractive avenue for presentation. However, how risk factors, in particular chronic gammaherpes virus infection, mechanistically impact MS risk or progression is unclear. These types of questions are very difficult, if not impossible, to address in studies in humans, and in this application, we propose to use animal models of MS. Mouse models offer powerful genetic tools, and allow for cause/effect mechanistic studies, but conventional mouse models are highly artificial and lack genetic diversity. We will use several novel mouse genetic models that are designed to better represent the complex genetic structure of human populations, which will allow us to dissect the complex genetic architecture underlying MS pathogenesis, to identify specific genes responsible for various poorly understood aspects of this disease, and to identify gene-by-environment interactions and novel mechanisms underlying environmental risk factors.