Epigenomic signaling and heart failure.

项目说明/摘要 心力衰竭的特征是体征和症状的持续发展。相对较长的间隔(几个 年)之间存在引起心肌损害的诱发事件和随后的功能代偿性 病程和最终状态称为扩张型心肌病。扩张型心肌病的特征是明显增大 心腔和收缩功能受损。描绘了启动和启动和 在这一漫长的间歇期内，介导心力衰竭的发病机制仍然是一个巨大的挑战，而且是长期的. 项目的学期目标。 一种普遍接受的心力衰竭发展模式将心力衰竭的病理过程分为两个截然不同的阶段 阶段：最初的代偿性肥大跟上身体对血液供应的需求，然后是危急的 在持续应激下过渡到失代偿性失效。 表观基因组调控正在作为一种新的机制而出现，有助于肿瘤的发生、发展和预后。 心力衰竭和下一代测序技术使剖析这一复杂的调控成为可能 机制。 在这项研究中，研究人员从一组无偏见的基因组规模的高通量筛查开始，这两个人 和动物衰竭的心脏，并发现了几个可能对进展至关重要的表观遗传调节因子 心力衰竭包括早期心肌肥厚和后期心力衰竭。一套全面的 应用生物信息学分析、分子生物学实验和遗传动物模型来研究这一新的 机制。最终的结果将使人们能够从不同的角度了解心力衰竭的进展。这个 操纵这一未被发现的机制可能是治疗心力衰竭患者的一种新的治疗策略。

PROJECT DESCRIPTION/ABSTRACT Heart failure is characterized by a relentless progression of signs and symptoms. A relatively long interval (several years) exists between the precipitating events that induce myocardial damage followed by a functional compensated period and the final state termed dilated cardiomyopathy. Dilated cardiomyopathy is characterized by markedly enlarged heart chambers and impaired contractile function. Delineating the molecular and cellular mechanisms that initiate and mediate the pathogenesis of heart failure during this long interval still remains an enormous challenge, and is the long- term goal of the project. A commonly accepted paradigm for the development of heart failure divides the pathological process into two distinct stages: initial compensatory hypertrophy to keep up with the body demand for blood supply, followed by a critical transition to decompensated failure under persistent stress. Epigenomic regulation is emerging as a new mechanism contributing to the initiation, development and prognosis of heart failure, and next-generation sequencing technologies have made it possible to dissect this complicated regulatory mechanism. In this study, the investigators started with a set of unbiased genome-scale high-throughput screenings in both human and animal failing hearts, and uncovered several potential epigenetic regulators that might be critical for the progression of heart failure including initial stage of cardiac hypertrophy and the later failing stage. A set of comprehensive bioinformatics analyses, molecular biology experiments and genetic animal models are applied to investigate this new mechanism. The eventual results will allow a look from a different angle to understand the progression of HF. The manipulation of the uncovered mechanism could be a novel therapeutic strategy for the heart failure treatment in patients.