A Systems Approach to Dissect Genetic Basis of Heart Failure

描述（申请人提供）：充血性心力衰竭是一种涉及多种遗传和环境因素的复杂疾病。三年前，专门研究心力衰竭的分子生物学家王宜宾博士和心血管疾病领域的遗传学家奥尔顿·卢西斯博士的实验室联手在杂交小鼠多样性小组（HMDP）中进行基因筛选，以确定导致常见心力衰竭的基因。在过去的两年中，这项工作得到了多PI R21的支持。这种支持使我们能够完成初步筛选，并确定了30多个全基因组范围内的重要基因座，这些基因座与慢性肾上腺素能激动剂异丙肾上腺素（ISO）刺激引起的心脏病理的不同方面有关，包括肥大、纤维化、心功能障碍和重构。此外，在对照小鼠和ISO处理后，获得了所有HMDP小鼠心脏的基因表达谱。这些丰富的数据集包含遗传信息，详细的心脏表型参数和来自107个近交系小鼠的综合心脏转录组谱，将使我们能够利用遗传学和系统方法的力量来识别有助于心力衰竭期间心脏病理特定方面的新分子途径。事实上，我们观察到所有HMDP菌株在ISO刺激后心力衰竭表型的显著差异，并发现了许多与心脏肥大和纤维化显著相关的遗传位点和基因模块。这些数据支持了一个总体假设，即常见的遗传变异对心力衰竭的发病机制起主要作用。通过系统方法揭示这些新发现的HF相关基因及其相互作用的机制基础是本提案的总体目标。具体来说，在目标1中，

DESCRIPTION (provided by applicant): Congestive heart failure is a complex disease involving multiple genetic and environmental factors. Three years ago, the laboratories of Dr. Yibin Wang, a molecular biologist with expertise in heart failure, and Dr. Aldons Lusis, a geneticist working in the area of cardiovascular disease, joined forces to perform a genetic screen in a hybrid mouse diversity panel (HMDP) to identify genes contributing to common forms of heart failure. For the past two years, this work has been supported by a multi- PI R21. This support enabled us to complete the preliminary screen and identified over 30 genome-wide significant loci harboring genes contributing to different aspects of cardiac pathologies induced by chronic stimulation of the ¿-adrenergic agonist isoproterenol (ISO), including hypertrophy, fibrosis, and cardiac dysfunction and remodeling. Moreover, gene expression profiles were obtained from all HMDP mouse hearts in control mice and following ISO treatment. These rich datasets containing genetic information detailed cardiac phenotype parameters and comprehensive cardiac transcriptome profiles from 107 inbred strains of mice will allow us to harness the power of genetics and systems approaches to identify novel molecular pathways contributing to the specific aspects of cardiac pathology during heart failure. Indeed, we observed a dramatic diversity of heart failure phenotypes among all HMDP strains following ISO stimulation and discovered a number of genetic loci and gene modules with significant association with cardiac hypertrophy and fibrosis. These data support the overall hypothesis that common genetic variants have a major contribution to the pathogenesis of heart failure. Uncovering the mechanistic basis of these newly discovered HF associated genes and their interactions via systems approach is the overarching goal of this proposal. Specifically, in Aim 1, we will extend our systems studies to discover genes and gene modules significantly associated with cardiac pathology induced by chronic angiotensin II treatment (AngII). We will identify unique and common genes involved in ¿AR vs. ¿AR-specific pathogenesis in heart. In Aim 2, we will investigate the molecular mechanisms underlying a candidate gene associated with heart failure, Miat, that encodes a long-non-coding (lnc)RNA with a previously unknown function in heart. In Aim 3, we will investigate the mechanism and functional role of Abcc6, a GWAS candidate gene, in stress induced cardiac fibrosis. These studies will reveal the underlying genetic contributions to specific features of heart failure, and the uncovered novel pathology associated genes and their interaction should provide new insights to the mechanism of the disease.