Novel mouse models to dissect the role of genetics, sex, and environment in heterogeneous outcomes in CNS autoimmune 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原发进展型多发性硬化症，后者高度衰弱和 难治性的。多发性硬化症在女性中的发病率是女性的三倍，但在男性中往往更严重。MS HAS 这是一个重要的可遗传成分，高达30%的疾病风险是由基因决定的。虽然是最近的 研究已经确定了与多发性硬化症风险相关的候选基因，目前尚不清楚这些基因如何 以及这些是否是真正的因果关系。此外，完全不清楚为什么有些人会患上 这种疾病的不同形式，以及为什么男性和女性之间存在差异。其他70%的 疾病风险来自环境或基因与环境的相互作用，这是一种有吸引力的途径 以供演示。然而，危险因素，特别是慢性伽马疱疹病毒感染，如何从机制上 影响多发性硬化症风险或进展尚不清楚。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，以及在这个应用中，我们建议使用女士的动物模型老鼠模型提供 强大的遗传工具，并允许因果机制研究，但传统的小鼠模型高度 人工的，缺乏遗传多样性。我们将使用几种新的小鼠遗传模型，这些模型旨在更好地 代表了人类种群的复杂遗传结构，这将使我们能够剖析复杂的遗传 MS发病机制的基础架构，以确定与各种鲜为人知的疾病相关的特定基因 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发病机制 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.