Genomics of myocardial transcription factors in cardiac remodeling

描述(由申请人提供)：心脏重构是人类心力衰竭的一个中心特征，并在人类受试者中显示出显著的差异。首席调查员在小鼠模型和人体上进行的十年研究表明，一组谨慎的心脏转录因子整合了应激信号，导致心脏重构。我们的中心假设是，一组核心心脏转录因子(MEF2、NKX、NFAT、GATA、FOX)的共同遗传变异在很大程度上导致了人类心脏重构的不同过程。我们将通过在两项现有的队列研究中对候选转录因子进行基于SNP和单倍型的关联研究来解决这一假设，这两项研究捕捉了临床实践中遇到的常见重塑表型。在目标1中，我们将在慢性肾功能不全队列研究(CRIC)中检验候选转录因子的变异与向心性心脏重构相关的假设，CRIC是一个向心性重构发生率较高的大型队列研究。在目标2中，我们将在宾夕法尼亚大学心力衰竭研究中进行类似的分析，这是一个由申请者发起的大型单中心队列，偏心重塑的发生率很高。在目标3中，我们将与宾夕法尼亚大学的专家分子生物学家Edward Morrisey博士合作，利用体外技术确定观察到的风险变量改变转录因子功能的机制。这项应用使用基因组方法直接研究患有常见心脏病的人类受试者的心脏转录因子。使用两个具有大样本量和定量超声心动图的已建立的队列将提供最终解决我们的假设所需的表型数据，并将利用已经在建立大型、良好表型队列方面所做的投资。通过将重点放在尚未在人类身上充分研究的动物模型中的核心重要因素上，我们的发现将把多年的基础研究转化为对人类心脏重构的机制理解。最重要的是，我们希望确定和验证心脏重构的基因组预测因子，这些因子可能作为预测预后和选择高危患者进行积极治疗的工具应用于临床。

DESCRIPTION (provided by applicant): Cardiac remodeling is a central feature of human heart failure and shows substantial variation in human subjects. A decade of research in murine models and research in humans performed by the Principal Investigator show that a discreet set of cardiac transcription factors integrate stress signals to cause cardiac remodeling. Our central hypothesis is that common genetic variation in a core set of cardiac transcription factors (MEF2, NKX, NFAT, GATA, FOX) is in large part responsible for the variable course of cardiac remodeling in humans. We will address this hypothesis by performing SNP- and haplotype-based association studies of candidate transcription factors in two existing cohort studies that capture the common phenotypes of remodeling encountered in clinical practice. In Aim 1 we will test the hypothesis that variation in candidate transcription factors is associated with concentric cardiac remodeling in the Chronic Renal Insufficiency Cohort study (CRIC), a large cohort with a high prevalence of concentric remodeling. In Aim 2 we will perform similar analyses in the Penn Heart Failure Study, a large single-center cohort initiated by the applicant with a high prevalence of eccentric remodeling. In aim 3 we will collaborate with an expert molecular biologist at Penn, Dr. Edward Morrisey, to determine the mechanisms by which the observed risk variants alter transcription factor function using in vitro techniques. This application uses genomic approaches to study cardiac transcription factors directly in human subjects with common forms of heart disease. The use of two established cohorts with large sample sizes and quantitative echocardiography will provide the phenotypic data necessary to address our hypotheses definitively, and will capitalize on investments already made in establishing large, well-phenotyped cohorts. By focusing on factors of central importance in animal models that have not been adequately studied in humans, our findings will translate years of basic research into a mechanistic understanding of human cardiac remodeling. Most importantly, we expect to determine and validate genomic predictors of cardiac remodeling that may have clinical applications as tools to predict prognosis and to select high-risk patients for aggressive therapy.