A Systems Approach to Dissect Genetic Basis of Heart Failure

描述（由申请人提供）：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，具有心力衰竭专业知识的分子生物学家Yibin Wang博士和心血管疾病领域的遗传学家Aldons Lusis博士的实验室联手在杂交小鼠多样性小组（HMDP）中进行遗传筛查，以确定导致常见形式心力衰竭的基因。在过去的两年里，这项工作得到了多PI R21的支持。这一支持使我们能够完成初步筛选，并确定了超过30个全基因组重要基因座，这些基因座含有导致肾上腺素能激动剂异丙肾上腺素（ISO）慢性刺激诱导的心脏病理学不同方面的基因，包括肥大、纤维化以及心脏功能障碍和重塑。此外，从对照小鼠和ISO处理后的所有HMDP小鼠心脏获得基因表达谱。这些丰富的数据集包含来自107个近交系小鼠的遗传信息、详细的心脏表型参数和全面的心脏转录组谱，将使我们能够利用遗传学和系统方法的力量来鉴定导致心力衰竭期间心脏病理学特定方面的新分子途径。事实上，我们在ISO刺激后观察到所有HMDP菌株中心力衰竭表型的显著多样性，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。这些数据支持这一总体假设，即常见的遗传变异对心力衰竭的发病机制有重大贡献。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。具体而言，在目标1中， 我们将扩展我们的系统研究，以发现与慢性血管紧张素II治疗（AngII）诱导的心脏病理学显著相关的基因和基因模块。我们将确定参与心脏AR与AR特异性发病机制的独特和共同基因。在目标2中，我们将研究与心力衰竭相关的候选基因Miat的分子机制，Miat编码一种在心脏中具有先前未知功能的长非编码（lnc）RNA。目的3：研究GWAS候选基因Abcc6在应激性心肌纤维化中的作用机制。这些研究将揭示潜在的遗传贡献的特定特征的心力衰竭，和发现新的病理相关基因和它们的相互作用应该提供新的见解，疾病的机制。

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.