Genetic Modulation of Hypertrophic Cardiomyopathy Severity

肥厚型心肌病严重程度的基因调节

基本信息

批准号：
9332400
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
项目类别：
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/9332400
关键词：
Affect Alleles Candidate Disease Gene Cardiac Myocytes Cardiovascular system Cause of Death 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 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 Statistical Models Sudden Death System Testing Translations Variant Work base cofactor cohort genetic variant genome wide association study high risk insertion/deletion mutation interstitial loss of function molecular modeling mutant novel strategies personalized care phenome phenotypic data reverse genetics screening trait transcriptome transcriptomics

Affect Alleles Candidate Disease Gene Cardiac Myocytes Cardiovascular system Cause of Death 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 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 Statistical Models Sudden Death System Testing Translations Variant Work base cofactor cohort genetic variant genome wide association study high risk insertion/deletion mutation interstitial loss of function molecular modeling mutant novel strategies personalized care phenome phenotypic data reverse genetics screening trait transcriptome transcriptomics

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项目摘要

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.

肥厚心肌病（HCM）临床表现的变异性主要由修饰符确定基因，不理解。发现差异脆弱性的遗传基础至关重要针对HCM患者的预测和个性化护理，将使更全面的遗传和基因组筛查的目的是尽早干预并消除猝死的风险。事实证明，发现有助于变异和不完整渗透率的修饰剂基因已被证明很困难在人类同伙中。现在，大型鼠遗传参考人群（GRP）最终提供了有效的解决方案。 BXD菌株家族（目前是最大，最佳的鼠标GRP）由160个高度组成从C57BL/6J（B6）和DBA/2J（D2）父母菌株之间的十字架下降的潜水线。 BXD 已经专门针对使用经典远期遗传学方法的系统遗传学研究而繁殖反向遗传研究。我们已经表明，D2（BXD十字架的父亲）是一个出色的鼠HCM 模型。 D2包含MYBPC3和MYH7的突变，HCM的主要休闲基因和关键特征人类HCM。相比之下，B6（BXD的母亲）具有野生型等位基因和正常心脏。目标我们的建议是确定影响HCM表型严重程度的修饰基因。我们的假设是修饰符和因果基因的相互作用控制HCM严重程度和相关表型。这里的研究涉及B6，D2和多达100 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，并导致识别强候选基因和网络 HCM表型中的个体差异。 AIM 1：系统量化与HCM相关的性状以及它们在100 BXD基因型的异源小鼠中的可变性和遗传力。目标1的目的是确定100个BXD菌株中的临床，实验室和分子HCM表型，为我们奠定了阶段探索目标2和3中HCM的遗传变异，辅助因子和机制。目标2：定义基因调节HCM的严重程度。基于AIM 1中生成的表型数据以及已经获得了B6和D2以及BXD的获取序列和转录组数据，我们将确定强大的基因变异使用最先进的系统遗传策略和常规的系统调节HCM表型的变异性分子和细胞测定。 AIM 3：测试小鼠HCM修饰符基因候选物的翻译有效性。我们将证明具有既定的HCM人类GWAS数据在AIM 2中确定的候选基因合理。在倒数中反向翻译，我们将评估来自人类人群的候选HCM基因，并确定这些是否是否变体与BXD中的HCM相关性状有关。结合最高优先基因候选者小鼠和人类HCM研究，我们将生成易感的分子和统计模型候选基因，连接的表型和相关机制。我们最终将验证调制HCM的基因使用损失功能策略的表型严重程度。