Epigenomic signaling and heart failure.

项目描述/摘要 心力衰竭的特征是体征和症状的持续进展。相对较长的间隔（几个 在诱发心肌损伤的诱发事件和随后的功能性代偿事件之间， 这一时期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 心室和收缩功能受损。描述了启动和 在这段长时间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， 项目的长期目标。 一种普遍接受的心力衰竭发展模式将病理过程分为两个不同的阶段， 阶段：最初的代偿性肥大，以跟上身体对血液供应的需求，其次是关键的 在持续应力下向失代偿失效的转变。 表观基因组调控作为一种新的机制正在出现，有助于启动，发展和预后， 心力衰竭，和下一代测序技术已经有可能剖析这种复杂的调控机制， 机制 在这项研究中，研究人员从一组无偏倚的基因组规模的高通量筛选开始， 和动物衰竭的心脏，并发现了几个潜在的表观遗传调节因子，可能是至关重要的进展 包括心肌肥厚初期和心力衰竭后期。一套全面的 本文应用生物信息学分析、分子生物学实验和遗传动物模型等方法对这一新的基因进行了研究。 机制最终的结果将允许从不同的角度来理解HF的进展。的 操纵未被揭示的机制可能是用于患者心力衰竭治疗的新的治疗策略。

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.