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/摘要 多发性硬化症（MS）是一种慢性疾病，是非创伤性神经疾病的主要原因 年轻人。该疾病是由于对中枢神经系统的异常免疫介导的攻击引起的， 会导致组织破坏并随后的神经系统疾病。疾病病程与 个人到个人，从复发的MS到主要的渐进式MS，后者高度衰弱， 对治疗难治性。 MS在女性中的常见三倍，但男性往往更为严重。 MS有 一个重要的可遗传成分，遗传确定了多达30％的疾病风险。最近 研究已经确定了与MS风险相关的候选基因，目前尚不清楚这些基因如何 工作以及这些是否真正是病因。此外，完全未知为什么有些人得到 这种疾病的不同形式，以及为什么男女之间存在差异。其他70％ 疾病风险来自环境或环境相互作用，代表着一个有吸引力的途径 用于演示。但是，危险因素如何，特别是慢性γ-病毒感染 影响MS风险或进展尚不清楚。这些类型的问题很难解决，即使不是不可能的问题 在人类的研究中，在此应用中，我们建议使用MS的动物模型。鼠标模型提供 强大的遗传工具，并允许有原因/效应机械研究，但是传统的鼠标模型高度高 人造和缺乏遗传多样性。我们将使用几种旨在改善的新型鼠标遗传模型 代表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发病机理的基础建筑，以识别负责各种差知识的特定基因 该疾病的各个方面，并鉴定基因与环境相互作用和基本的新机制 环境风险因素。