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

新型小鼠模型可剖析遗传、性别和环境在中枢神经系统自身免疫性疾病异质性结果中的作用

• 批准号: 10680560
• 负责人: Dimitry N Krementsov
• 金额: $ 52.11万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680560
• 关键词: Address; Affect; Alleles; Animal Model; Autoimmune Diseases; Autoimmunity; Automobile Driving; Axon; CD4 Positive T Lymphocytes; CNS autoimmune disease; Candidate Disease Gene; Cell Reprogramming; Cells; Central Nervous System; Chromosome Mapping; Chromosomes; Chronic; Chronic Disease; Complex; Control Locus; Data; Demyelinations; Disease; Disease Progression; Dissection; Down-Regulation; Environment; Environmental Risk Factor; Epstein-Barr Virus Infections; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Designs; Failure; Funding; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Structures; Genetic Variation; Genotype; Gliosis; Heritability; Heterogeneity; Human; Human Herpesvirus 4; Immune; Immunization; Immunologics; In Vitro; Inbred Strains Mice; Incidence; Individual; Infection; Infectious Diseases Research; Knowledge; Machine Learning; Maps; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Neurologic; Neurologic Dysfunctions; Orthologous Gene; Outcome; Pathogenesis; Pathology; Phenotype; Population; Predisposition; Primary Progressive Multiple Sclerosis; Publishing; Quantitative Trait Loci; Refractory; Relapsing-Remitting Multiple Sclerosis; Resources; Risk; Risk Factors; Role; Severities; Sex Differences; System; Tissues; Transgenic Mice; Validation; Viral Load result; Virus; Virus Diseases; Virus Replication; Vitamin D; Woman; Work; candidate identification; chronic autoimmune disease; chronic infection; clinical phenotype; consomic; design; disability; disorder control; disorder risk; gene environment interaction; genetic approach; genetic architecture; genome wide association study; gut microbiota; high risk; human disease; human model; immunoregulation; lead candidate; men; model design; mouse genetics; mouse model; novel; pharmacologic; sex; tool; trait; virtual; 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, 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.

项目摘要/总结 多发性硬化症 (MS) 是一种慢性疾病，是导致非创伤性神经功能障碍的主要原因 年轻人。该疾病是由免疫介导的中枢神经系统异常攻击引起的， 这会导致组织破坏和随后的神经功能障碍。病程差异很大 从复发缓解型多发性硬化症到原发性进行性多发性硬化症，后者使人高度衰弱， 难以治疗。多发性硬化症在女性中的发病率是女性的三倍，但在男性中往往更为严重。女士有 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 研究已经确定了与多发性硬化症风险相关的候选基因，但目前尚不清楚这些基因如何 工作以及这些是否确实是造成这种情况的原因。此外，完全不知道为什么有些人会得到 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 MS 风险或进展的影响尚不清楚。解决这些类型的问题即使不是不可能，也是非常困难的 在人类研究和本应用中，我们建议使用多发性硬化症动物模型。鼠标型号优惠 强大的遗传工具，并允许进行因果机制研究，但传统的小鼠模型高度 人工的，缺乏遗传多样性。我们将使用几种新颖的小鼠遗传模型，旨在更好地 代表了人类复杂的遗传结构，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，以确定负责各种知之甚少的特定基因 该疾病的各个方面，并确定基因与环境的相互作用和潜在的新机制 环境风险因素。