Genetic Risk Factors of Myocyte Contractility in Human Heart Failure

描述（由申请人提供）：美国约有500万患者患有心力衰竭，每年诊断出超过50万新患者。患有最晚期心力衰竭的个体对最佳药物治疗没有反应。这项发现R21应用的目的是使用一种创新的方法来定位破坏microRNA（miRNA）结合位点的单核苷酸多态性（SNP），以识别心力衰竭个体中的一类新的调控突变。这些SNP可能抑制miRNA结合或产生新的miRNA结合位点。待检验的假设是，调节肌细胞收缩性和舒张性的基因的miRNA结合位点中的SNP与早发性扩张型心肌病和晚期心力衰竭的风险增加相关。这些实验利用了来自接受心室辅助装置（VAD）或心脏移植的患者的库存和新鲜人体组织的独特资源。该策略的优势在于同时鉴定生物学机制的高概率，通过该生物学机制鉴定的SNP影响遗传风险。获取新获得的人体组织允许测量肌细胞收缩性。我们提出以下具体目标：在早发性扩张型心肌病和晚期心力衰竭患者中，确定与肌节功能和钙处理相关的基因的miRNA结合位点中的新SNP关联。具体目标二。确定与肌节功能和钙处理相关的基因的miRNA结合位点中SNP对来自核心活检的分离心肌细胞的肌细胞收缩性和舒张性的作用。 公共卫生相关性：该提案中概述的实验将测试一种创新方法，以确定心力衰竭个体中microRNA结合位点的一类新的调控突变。这些突变可能会破坏microRNA结合或产生新的microRNA结合位点。

DESCRIPTION (provided by applicant): Approximately 5 million patients in the United States have heart failure and over 500,000 new patients are diagnosed each year. Individuals with the most advanced stage of heart failure do not respond to optimal medical therapy. The purpose of this discovery R21 application is to identify a new class of regulatory mutations in individuals with heart failure using an innovative approach to map single nucleotide polymorphisms (SNPs) that disrupt microRNA (miRNA) binding sites. These SNPs may inhibit miRNA binding or create new miRNA binding sites. The hypothesis to be tested is that SNPs in miRNA binding sites of genes that regulate myocyte contractility and relaxation are associated with increased risk of early onset dilated cardiomyopathy and advanced heart failure. These experiments leverage a unique resource of banked and fresh human tissue from patients receiving a ventricular assist device (VAD) or heart transplant. A strength of this strategy is the high probability of simultaneously identifying the biological mechanism through which the identified SNPs influence genetic risk. Access to newly procured human tissue permits measurements of myocyte contractility. We propose the following specific aims: Specific Aim I. Identify new SNP associations in miRNA binding sites of genes associated with sarcomere function and calcium handling in individuals with early onset dilated cardiomyopathy and advanced heart failure. Specific Aim II. Identify the role of SNPs in miRNA binding sites of genes associated with sarcomere function and calcium handling on myocyte contractility and relaxation in isolated cardiac myocytes from core biopsies. PUBLIC HEALTH RELEVANCE: Experiments outlined in this proposal will test an innovative approach to identify a new class of regulatory mutations in microRNA binding sites in individuals with heart failure. These mutations may disrupt microRNA binding or create new microRNA binding sites.