Host genetic determinants of diversity in viral-induced neuropathology

病毒诱导的神经病理学多样性的宿主遗传决定因素

基本信息

批准号：
10055969
负责人：
Candice L. Brinkmeyer-Langford
金额：
$ 32.03万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055969
关键词：
Address Affect Alleles Candidate Disease Gene Categories Characteristics Clinical Complex Data Demyelinations Development Disease Disease Outcome Enzyme-Linked Immunosorbent Assay Epilepsy Evidence based treatment Family Picornaviridae Future Genetic Genetic Determinism Genetic Polymorphism Genetic Variation Genome Genomics Goals Group Identifications Haplotypes Heterogeneity Histology Human Immune response Inbred Strains Mice Individual Infection Intervention Knowledge Lead Link Literature Major Histocompatibility Complex Mission Modeling Mouse Strains Multiple Sclerosis Mus Neurologic Neurological outcome Outcome Pathogenesis Pathogenicity Pathology Phenotype Population Predisposition Preventive Preventive treatment Public Health Publishing Quantitative Trait Loci Research Resources Role System TMEV Testing United States National Institutes of Health Variant Viral Viral Pathogenesis Virus Virus Diseases adverse outcome base behavioral phenotyping cytokine disability disease phenotype genetic analysis genetic variant genomic variation individual variation individualized medicine influenza infection innovation insight mouse model nervous system disorder neurological pathology neuropathology neurotropic novel pathogenic virus personalized intervention population based predictive modeling resistant strain response tool transcriptome sequencing virus-induced demyelination

项目摘要

PROJECT SUMMARY Infection by a given virus can cause diverse neurological outcomes and disease pathologies, influenced by the genetic background of the host. In mice, Theiler's murine encephalomyelitis virus (TMEV) infection leads to heterogeneous neurological conditions, depending on mouse strain infected. Because of the relevance of TMEV infection as a tool for studying virally-influenced neurological conditions in humans, there is a critical need to determine genetic variants and their mechanisms that link TMEV infection to disease outcome. The long-term goal is to identify and characterize environmental and genetic interactions that contribute to individual variation in response to viral infection. The objective of this application is to determine how genetic background influences disease diversity following TMEV infection. The central hypothesis is that genetic background, as modeled by a new population-based mouse model, will differentially modify susceptibility to TMEV-induced diseases based upon genetic polymorphisms. The rationale for the proposed research is that a delineation of the genetic effects underlying the diverse outcomes of TMEV infection is likely to contribute new insights into the heterogeneity of virally induced human neurological conditions. The hypothesis will be tested with three specific aims: 1) Evaluate strains of the Collaborative Cross (CC) mouse resource for phenotypic variation in response to TMEV infection, 2) Evaluate host genome regions for associations with TMEV-induced phenotypes, and 3) Identify phenotypic modules governed by shared mechanisms. Aim 1 is based on published and preliminary data showing that TMEV infection causes diverse outcomes depending on the genetic background of the mouse. Neurological and behavioral phenotyping tests, ELISAs, and histology will be used to test the hypothesis that the disease pathologies of TMEV infection in different CC mice demonstrate a hierarchy, to facilitate the identification of groups of mice with similar characteristics that can be linked to genetically-diverse CC lines. For Aim 2, RNA sequencing and QTL analyses will be used to test the hypothesis that genomic diversity within CC mice influences variable disease phenotypes. In Aim 3, cytokine analyses, modularity clustering and candidate gene allele association will be used to test the hypothesis that the phenotypic diversity among CC strains can be clustered into modules which can be used to identify shared mechanisms. Our contribution here is expected to be an understanding of the genetic determinants responsible for phenotypic diversity following TMEV infection using the CC population of mice. The proposed research is innovative because it uses an experimental mouse model that captures the breadth of genetic diversity typically found in human populations, thus comprehensively addressing host contributions to virally influenced neurological conditions. This research is significant because it is expected to constitute an early step in a continuum of research that will increase knowledge about virally influenced complex neurological conditions in humans and ultimately lead to the development of novel predictive models and therapies.

项目摘要给定病毒感染会引起多种神经系统结局和疾病病理，受到影响宿主的遗传背景。在小鼠中，Theiler的鼠脑脊髓炎病毒（TMEV）感染导致异质性神经条件，具体取决于感染小鼠菌株。因为 TMEV感染是研究人类病毒影响的神经系统疾病的工具，存在关键需要确定将TMEV感染与疾病结局联系起来的遗传变异及其机制。这长期目标是识别和表征有助于的环境和遗传相互作用响应病毒感染的个体变异。该应用的目的是确定遗传背景会影响TMEV感染后的疾病多样性。中心假设是遗传背景是由新的基于人群的鼠标模型建模的，将差异地改变对基于遗传多态性的TMEV诱导的疾病。拟议研究的理由是划定TMEV感染的多种结果的遗传效应可能有助于新的对病毒诱导的人类神经系统疾病的异质性的见解。该假设将进行检验具有三个具体目的：1）评估协作交叉（CC）鼠标资源的菌株用于表型响应TMEV感染的变化，2）评估与TMEV诱导的关联的宿主基因组区域表型和3）确定由共享机制控制的表型模块。 AIM 1基于已发布和初步数据，表明TMEV感染会导致多种结果小鼠的遗传背景。神经和行为表型测试，ELISA和组织学将用于检验以下假设：不同CC小鼠中TMEV感染的疾病病理表明层次结构，以促进具有相似特征的小鼠组的识别，可以链接到遗传多样性CC线。对于AIM 2，将使用RNA测序和QTL分析来检验假设 CC小鼠中的基因组多样性会影响可变疾病表型。在AIM 3中，细胞因子分析，模块化聚类和候选基因等位基因关联将用于检验以下假设。 CC菌株之间的表型多样性可以聚集到可用于识别共享的模块中机制。我们在这里的贡献预计将是对遗传决定因素的理解使用小鼠的CC群体在TMEV感染后负责表型多样性。提议研究具有创新性，因为它使用了捕获遗传广度的实验鼠标模型多样性通常在人类种群中发现，因此可以全面解决宿主对病毒的贡献影响神经系统状况。这项研究很重要，因为预计它将构成早期逐步进行一系列研究，将增加有关受病毒影响复杂神经系统的知识人类的条件并最终导致新型预测模型和疗法的发展。