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.

项目概要特定病毒的感染可导致不同的神经系统结果和疾病病理，受宿主的遗传背景。在小鼠中，泰勒氏鼠脑脊髓炎病毒 (TMEV) 感染会导致不同的神经系统疾病，取决于感染的小鼠品系。由于相关性 TMEV 感染作为研究人类受病毒影响的神经系统疾病的工具，有一个关键需要确定将 TMEV 感染与疾病结果联系起来的遗传变异及其机制。这长期目标是识别和描述有助于对病毒感染的反应存在个体差异。该应用程序的目的是确定遗传如何背景影响TMEV感染后的疾病多样性。中心假设是遗传以新的基于群体的小鼠模型为模型的背景，将差异性地改变对以下疾病的易感性：基于遗传多态性的 TMEV 诱发疾病。拟议研究的基本原理是描述 TMEV 感染的不同结果背后的遗传效应可能会带来新的结果深入了解病毒引起的人类神经系统疾病的异质性。假设将被检验具有三个具体目标：1) 评估协作杂交 (CC) 小鼠资源品系的表型对 TMEV 感染的反应变化，2) 评估宿主基因组区域与 TMEV 诱导的关联表型，以及 3) 识别由共享机制控制的表型模块。目标 1 是基于已发表的初步数据表明，TMEV 感染会导致不同的结果，具体取决于小鼠的遗传背景。神经学和行为表型测试、ELISA 和组织学将用于检验不同 CC 小鼠中 TMEV 感染的疾病病理学证明的假设层次结构，以方便识别具有相似特征的小鼠组，这些特征可以链接到遗传多样性的 CC 系。对于目标 2，将使用 RNA 测序和 QTL 分析来检验假设 CC 小鼠的基因组多样性影响不同的疾病表型。在目标 3 中，细胞因子分析，模块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类成模块，这些模块可用于识别共享的机制。我们在这里的贡献预计是对遗传决定因素的理解负责使用 CC 小鼠群体进行 TMEV 感染后的表型多样性。拟议的研究具有创新性，因为它使用了实验小鼠模型来捕捉遗传的广度通常存在于人群中的多样性，从而全面解决宿主对病毒的贡献影响神经系统状况。这项研究意义重大，因为它有望构成早期连续研究的一步将增加对受病毒影响的复杂神经系统的了解人类的条件并最终导致新的预测模型和疗法的发展。