Genetic Modulation of Hypertrophic Cardiomyopathy Severity

肥厚型心肌病严重程度的基因调节

• 批准号: 9173710
• 负责人: LU LU
• 金额: $ 49.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173710
• 关键词: Affect; Alleles; Breeding; Candidate Disease Gene; Cardiac Myocytes; Cardiovascular system; Cellular Assay; Clinical; Collaborations; Complex; Data; Detection; Diagnostic; Disease; Dissection; Family; Fathers; Fibrosis; Gene-Modified; Genes; Genetic; Genetic Screening; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Heart; Heart Diseases; Heritability; Heterogeneity; Human; Human Chromosomes; Human Genome; Hypertrophic Cardiomyopathy; Hypertrophy; Individual Differences; Inherited; Laboratories; Lead; Link; Maps; Methods; Modeling; Molecular; Molecular Models; Mothers; Mus; Mutation; Parents; Patients; Penetrance; Phenotype; Population; Prevention; Publications; Quantitative Trait Loci; Research; Research Personnel; Risk; Severities; Severity of illness; Staging; Statistical Models; Sudden Death; System; Testing; Translations; Variant; Work; base; cofactor; cohort; genetic variant; genome wide association study; high risk; interstitial; loss of function; molecular modeling; mutant; novel strategies; personalized care; phenome; reverse genetics; screening; trait; transcriptome sequencing; transcriptomics

Variability in hypertrophic cardiomyopathy (HCM) clinical manifestation is primarily determined by modifier genes, which are poorly understood. Discovering of the genetic basis of differential vulnerability is critical in predictive and personalized care for patients with HCM and will enabling more comprehensive genetic and genomic screening with an aim to intervene as early as possible and eliminate risk of sudden death. The discovery of modifier genes that contribute to variation and incomplete penetrance of HCM has proven difficult in human cohorts. Large murine genetic reference populations (GRPs) now finally provide a effective solution. The BXD family of strains—currently the largest and best characterized mouse GRP—is made up of 160 highly diverse lines that descend from crosses between C57BL/6J (B6) and DBA/2J (D2) parental strains. The BXDs have been bred specifically for systems genetics studies using both classic forward genetic methods and for reverse genetic studies. We have shown that the D2—father of the BXD cross—is an excellent murine HCM model. D2 contains mutations of Mybpc3 and Myh7, the major causal genes of HCM and the key features of human HCM. In contrast, the B6 (mother of the BXDs) has wild type alleles and normal hearts. The objective of our proposal is to identify modifier genes that affect the severity of HCM phenotypes. Our hypothesis is that interactions of modifier and causal genes govern HCM severity and related phenotypes. The research here involves multi-scale genetic, transcriptomic, molecular and cellular profiling of B6, D2, and up to 100 BXDs. This work will be transformative and lead to the identification of strong candidate genes and networks underlying individual differences in HCM phenotypes. Aim 1: Systematically quantify HCM-associated traits and their variability and heritability across 100 BXD genotypes of isogenic mice. The purpose of Aim 1 is to determine the clinical, laboratory and molecular HCM phenotypes in 100 BXD strains, setting the stage for us to explore genetic variation, cofactors, and mechanisms of HCM in Aims 2 and 3. Aim 2: Define genes that modulate the severity of HCM. Building upon the phenotype data generated in Aim 1, as well as the already acquired sequence and transcriptome data for B6 and D2, and BXDs, we will identify strong gene variants that modulate variability of HCM phenotypes using state-of-the-art system genetic strategies and conventional molecular and cellular assays. Aim 3: Test the translational validity of mouse HCM modifier gene candidates. We will justify candidate genes identified in Aim 2 with established HCM human GWAS data. In reciprocal reverse translation, we will evaluate candidate HCM genes from human cohorts and determine whether these variants are associated with HCM-associated traits in BXDs. Combining the top priority gene candidates from both mouse and human HCM studies, we will generate molecular and statistical models of susceptible candidate genes, linked phenotypes, and relevant mechanisms. We will finally validate genes modulating HCM phenotype severity using loss-off function strategy.

肥厚型心肌病 (HCM) 临床表现的变异性主要由修饰因子决定 发现差异脆弱性的遗传基础至关重要。 为 HCM 患者提供预测性和个性化护理，并将实现更全面的遗传和 基因组筛查，旨在尽早干预并消除猝死风险。 发现导致 HCM 变异和不完全外显的修饰基因已被证明是困难的 大型小鼠遗传参考群体（GRP）现在终于提供了有效的解决方案。 BXD 品系家族——目前最大且特征最好的小鼠 GRP——由 160 个高度 由 C57BL/6J (B6) 和 DBA/2J (D2) 亲本品系杂交后代的不同品系。 是专门为系统遗传学研究而培育的，使用经典的正向遗传方法和 反向遗传学研究表明，D2（BXD 杂交之父）是一种优秀的小鼠 HCM。 D2 包含 Mybpc3 和 Myh7 突变，这是 HCM 的主要致病基因和关键特征。 相比之下，B6（BXD 的母亲）具有野生型等位基因和正常心脏。 我们的建议是确定影响 HCM 表型严重程度的修饰基因。 修饰基因和因果基因的相互作用控制 HCM 的严重程度和相关表型。 涉及 B6、D2 和多达 100 个 BXD 的多尺度遗传、转录组、分子和细胞分析。 这项工作将具有变革性，并导致识别强大的候选基因和网络 HCM 表型的潜在个体差异 目标 1：系统量化 HCM 相关特征。 及其在 100 个 BXD 基因型同基因小鼠中的变异性和遗传力 目标 1 的目的是 确定 100 个 BXD 菌株的临床、实验室和分子 HCM 表型，为我们奠定了基础 探索目标 2 和 3 中 HCM 的遗传变异、辅助因子和机制。目标 2：定义能够 基于目标 1 中生成的表型数据以及已有的表型数据来调节 HCM 的严重程度。 获得了 B6 和 D2 以及 BXD 的序列和转录组数据后，我们将识别出强大的基因变异 使用最先进的系统遗传策略和传统方法调节 HCM 表型的变异性 目标 3：测试小鼠 HCM 修饰基因候选物的翻译有效性。 我们将用已建立的 HCM 人类 GWAS 数据来证明目标 2 中确定的候选基因的合理性。 反向翻译，我们将评估来自人类队列的候选 HCM 基因，并确定这些基因是否 变体与 BXD 中的 HCM 相关性状相关，结合来自 BXD 的最优先候选基因。 在小鼠和人类 HCM 研究中，我们将生成脆弱性的分子和统计模型 我们将最终验证调节 HCM 的基因。 使用丧失功能策略的表型严重程度。