Epigenomic signaling and heart failure.

表观基因组信号和心力衰竭。

基本信息

批准号：
10310475
负责人：
Jiang Chang
金额：
$ 48.58万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-06 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310475
关键词：
ATAC-seq Age Aging Angioplasty Animal Genetics Animal Model Animals Antibodies Attenuated Bioinformatics Biological Assay Cardiac Cardiac Myocytes Cardiomegaly Cell Death Signaling Process ChIP-seq Chromatin DNA Methylation DNA Modification Methylases DNA Polymerase II DNA-Directed RNA Polymerase DNMT3B gene Data Dependovirus Development Dilated Cardiomyopathy Down-Regulation Epigenetic Process Event Exhibits Exons Failure Functional disorder Gene Expression Profile Genes Genetic Transcription Genetic Translation Goals Heart Heart Hypertrophy Heart failure High-Throughput Nucleotide Sequencing Histone H3 Human Hypertrophy Impairment Knock-out Knockout Mice Lead Left Lysine Maps Measurement Measures Mediating Medicine Modernization Modification Molecular Molecular Biology Mus Myocardial Infarction Necrosis Pathogenesis Pathologic Processes Pathway Analysis Pathway interactions Patients Pharmacological Treatment Phenotype Prevalence Prevention Prognosis Regulation Repression Research Personnel Resistance Resolution Role SET Domain Signal Transduction Signs and Symptoms Stress Technology Testing Time Tissues Transcript Transcription Initiation Transcription Initiation Site Transcriptional Activation Transgenic Mice Transposase Treatment Failure Vascular blood supply Ventricular Wild Type Mouse aging population base cardiogenesis chromatin immunoprecipitation cohort constriction epigenomics experimental study gain of function genome-wide heart function high throughput screening histone methylation improved insight mortality mouse model myocardial damage new therapeutic target next generation next generation sequencing novel novel therapeutic intervention overexpression pressure prevent recruit ribosome profiling transcriptome sequencing

项目摘要

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.

项目描述/摘要心力衰竭的特点是体征和症状不断进展。间隔时间比较长（几个年）存在于诱发心肌损伤的突发事件和随后的功能代偿之间期和最终状态称为扩张型心肌病。扩张型心肌病的特点是心脏明显增大心室和收缩功能受损。描述启动和启动的分子和细胞机制在这么长的时间间隔内介导心力衰竭的发病机制仍然是一个巨大的挑战，并且是长期的项目的长期目标。心力衰竭发展的普遍接受的范式将病理过程分为两个不同的过程阶段：最初的代偿性肥大以满足身体对血液供应的需求，随后是关键的阶段在持续压力下过渡到失代偿性衰竭。表观基因组调控正在成为一种有助于疾病发生、发展和预后的新机制。心力衰竭和下一代测序技术使得剖析这种复杂的监管成为可能机制。在这项研究中，研究人员首先对人类和人类进行了一系列无偏见的基因组规模高通量筛选。和动物衰竭心脏，并发现了几种可能对进展至关重要的潜在表观遗传调节因子心力衰竭包括初期心脏肥大和后期衰竭阶段。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。最终结果将允许从不同的角度观察心力衰竭的进展。这对未发现的机制的操纵可能是治疗患者心力衰竭的一种新的治疗策略。