Integrative genomics of human heart failure

描述(申请人提供)：心力衰竭(HF)是工业化国家成人住院的主要原因，给公共卫生带来了巨大的负担。在过去的二十年里，大量使用转基因模型的研究表明，越来越多的转录因子和microRNAs作为心肌肥大和功能障碍的中介。由于这些介体在人类心脏中被证实的很少，在将这些见解应用于人类心力衰竭治疗方面进展甚微。我们计划通过利用三个美国移植中心的独特生物资源来克服这些障碍，这三个中心在过去15年里积累了1900多名人类受试者的高质量心肌库。这项建议的总体目标是使用整合基因组学来测试动物模型中确定的转录调控程序是否与人类心力衰竭相关，并对受试者的心肌基因表达调控进行无偏见的筛选。综合基因组学通过将表型数据与感兴趣组织中的全基因组基因型和基因表达相结合来阐明疾病的机制。为了将这些方法应用于人类心脏，我们组建了一个由心力衰竭、临床调查、心脏生物学和复杂疾病遗传学方面的多学科专家组成的团队。在目标1中，我们将使用整合的SNP和表达数据进行一项病例对照研究(n=1000)，以测试40个预先指定的转录调控因子中的哪些与人类晚期心力衰竭有关。在目标2中，我们将进行一项横断面研究(n=1000)，使用整合的SNP和广泛心肌表型的表达数据来测试相同的候选调节因子是否对病理重塑起作用。在这两个目标中，二次分析和网络建模将使全基因组筛选人类心脏转录调控的意外机制成为可能。在目标3中，我们将测试我们最有希望的结果是否通过与Echogen的合作在普通人群中确定心脏重构的遗传风险因素，Echogen是一项对7个基于社区的队列(N=18,000)的超声心动图特征进行的全基因组关联荟萃分析。这项研究将检验来自多年动物研究的知识的相关性，同时采用公正的发现方法来揭示人类心肌疾病的意想不到的机制。这样做将加速科学知识向心衰疗法的转化。此外，将向科学界提供所有数据和生物样本，以促进对HF研究产生广泛和持久的影响。

DESCRIPTION (provided by applicant): Heart failure (HF) is the leading cause of adult hospitalization in the industrialized world and imposes a substantial burden on the public health. Over the past two decades, a large body of research using transgenic models has implicated a growing number of transcription factors and microRNAs as mediators of myocardial hypertrophy and dysfunction. Because few of these mediators have been confirmed in human hearts, there has been minimal progress in applying these insights to human HF therapeutics. We propose to overcome these barriers by leveraging unique bioresources at three U.S. transplant centers that have amassed repositories of high-quality myocardium from more than 1,900 human subjects over the past 15 years. The overall goals of this proposal are to use integrative genomics to test whether transcriptional regulatory programs identified in animal models are relevant in human HF and to perform unbiased screens for regulators of myocardial gene expression in human subjects. Integrative genomics elucidates disease mechanism by combining phenotype data with whole-genome genotypes and gene expression in a tissue of interest. To apply these approaches to the human heart, we have assembled a multidisciplinary team of experts in heart failure, clinical investigation, cardiac biology, and the genetics of complex disorders. In Aim 1, we will perform a case-control study (n=1000) using integrated SNP and expression data to test which of 40 pre-specified transcriptional regulators contribute to advanced HF in humans. In Aim 2, we will perform a cross-sectional study (n=1000) using integrated SNP and expression data across a broad range of myocardial phenotypes to test whether the same candidate regulators contribute to pathological remodeling. In both aims, secondary analyses and network modeling will enable genome-wide screens for unanticipiated mechanisms of transcriptional regulation in the human heart. In Aim 3, we will test whether our most promising results identify genetic risk factors for cardiac remodeling in the general population through collaboration with EchoGen, a genome-wide association meta-analysis of echocardiographic traits in seven community-based cohorts (N=18,000). This research will test the relevance of knowledge derived from years of animal research while employing an unbiased discovery approach to reveal unanticipated mechanisms of human myocardial disease. Doing so will accelerate the translation of scientific knowledge to HF therapeutics. Moreover, all data and biosamples will be made available to the scientific community to promote a broad and durable impact on HF research.