Regulation of Chromatin Signaling in Heart Failure by BET Bromodomain Proteins

BET 溴结构域蛋白对心力衰竭中染色质信号传导的调节

基本信息

批准号：
9042034
负责人：
JAMES E BRADNER
金额：
$ 88.17万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042034
关键词：
Acetylation Address Adult Affect Area BRD2 gene Bromodomain Cardiac Cardiac Myocytes Chromatin Clinical Country Data Development Diagnosis Disease Distal Enhancers Enzymes Epigenetic Process Event Expenditure Family Family member Gene Expression Genes Genetic Transcription Health Healthcare Heart Heart Hypertrophy Heart Research Heart failure Histone Deacetylase Histone Deacetylase Inhibitor Histones Hospitalization Human Hypertrophy In Vitro Knowledge Left Ventricular Remodeling Light Lysine Mediating Medical Research Messenger RNA Mission Modeling Molecular Mus Myocardial Myocardial tissue Myocardium Nodal Paper Pathogenesis Pathologic Pathology Pathway interactions Pharmaceutical Preparations Physiological Play Polymerase Positioning Attribute Positive Transcriptional Elongation Factor B Process Protein Isoforms Proteins Public Health Publishing Quality of life RNA Polymerase II Reader Recruitment Activity Regulation Regulator Genes Regulatory Element Research Rodent Model Role Signal Transduction Site Stream Stress Structure Tail Testing Therapeutic Transcriptional Regulation United States base cardiovascular disorder therapy chromatin remodeling clinically relevant coronary fibrosis design disability epigenomics genome-wide histone acetyltransferase improved in vivo inhibitor/antagonist innovation interest knock-down left ventricular assist device mortality mouse model new therapeutic target novel novel therapeutics pressure prevent programs small molecule small molecule inhibitor standard of care transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Despite current standard of care, a diagnosis of heart failure (HF) is associated with poor quality-of-life and a 5-year mortality approaching 50%. In light of this urgent unmet need, the elucidation of novel mechanisms involved in HF pathogenesis holds promise for identifying new therapies for this prevalent and deadly disease. The PIs of this application were the first to illustrate a crucial role for a conserved family of acetyl-lysine "reader" proteins (BET bromodomains) in the transcriptional control of pathological cardiac hypertrophy and HF. Importantly, these studies leveraged the use of JQ1, a first-in-class, specific small molecule inhibitor of BET bromodomains. This multi-PI application seeks to vertically advance our understanding of how aberrant chromatin dependent signal transduction (via the BET family member BRD4) drives pathologic cardiac remodeling. Our long-term objective is to develop BET bromodomain inhibition as a novel therapeutic strategy in HF. Exciting preliminary studies demonstrate that BRD4 mediates cardiomyocyte (CM) hypertrophy in vitro and that BET inhibition with JQ1 potently suppresses the development of pressure-overload mediated cardiac hypertrophy in mice. Mechanistically, we demonstrate that BRD4 occupies active enhancers in the adult mouse heart, recruits PTEF-b activity to transcriptional start sites, and triggers pause-release of RNA Polymerase II to activate genes critical for HF pathogenesis. Intriguingly, we demonstrate that pathologic stress leads to specific accumulation of BRD4 protein in CMs without any increase in Brd4 mRNA. Finally, we demonstrate that class I HDACs, which are generally pro-hypertrophic, are specifically required for BRD4 protein accumulation. Based on this rationale, this proposal will test the central hypothesis that BRD4 functions as a nodal transcriptional regulator of pathological cardiac remodeling that can be pharmacologically targeted in vivo. Guided by strong preliminary data, this hypothesis will be tested by pursuing three robust specific aims: (1) Elucidate the effects of BET inhibition in clinically relevant models of HF and during physiological cardiac plasticity; (2) Dissect the transcriptional mechanisms by which BRD4 drives dynamic enhancer remodeling, chromatin-dependent signal transduction, and selective gene control during cardiac stress; (3) Define the mechanisms by which HDACs crosstalk with BET proteins to integrate upstream signals with pro-hypertrophic gene expression in the heart. The proposed research is significant because it seeks to develop pharmacologic BET bromodomain inhibition as a novel therapeutic strategy in HF, and therefore addresses an enormous unmet clinical need. Our proposal is highly innovative because we successfully "drug" pathologic myocardial transcription and remodeling via an unprecedented approach. Given the synergistic expertise of our consortium, we envision that sustained contributions from our highly-collaborative group will pave the way for the development of novel "epigenetic therapies" for cardiovascular disease.

描述（通过应用程序提供）：尽管当前的护理标准，但心力衰竭（HF）的诊断与生活质量差和5年死亡率相关，接近50％。鉴于这种紧迫的未满足需求，阐明HF发病机理中涉及的新机制有望识别这种普遍和致命疾病的新疗法。该应用的PI是第一个说明在病理心脏肥大和HF的转录控制中保守的乙酰赖氨酸“读取器”蛋白（BET溴化群）家族的关键作用。重要的是，这些研究利用了JQ1的使用，JQ1是BET溴结构域的第一类，特定的小分子抑制剂。该多PI应用程序旨在垂直提高我们对异常染色质信号转导（通过BET家族成员BRD4）如何推动病理心脏重塑的理解。我们的长期目标是将BET BET溴化群抑制作用作为HF中的一种新型治疗策略。令人兴奋的初步研究表明，BRD4在体外介导心肌细胞（CM）肥大，而JQ1的抑制作用可能会抑制小鼠压力重载介导的心脏肥大的发展。从机械上讲，我们证明BRD4在成年小鼠心脏中占据了活跃的增强子，将PTEF-B活性募集到转录起始位点，并触发RNA聚合酶II的暂停释放，以激活对HF发病机理至关重要的基因。有趣的是，我们证明了病理胁迫会导致BRD4蛋白在CMS中的特异性积累，而BRD4 mRNA没有任何增加。最后，我们证明了BRD4蛋白的积累特别需要的，通常是亲脑的I类HDACs。基于此基本原理，该提案将检验一个中心假设，即BRD4是病理心脏重塑的淋巴结转录调节剂，可以在药理中靶向体内。在强大的初步数据的指导下，将通过追求三个强大的特定目的来检验该假设：（1）阐明在HF临床相关模型以及在物理心脏可塑性期间，BET抑制作用的影响；（2）剖析BRD4在心脏应激期间驱动动态增强子重塑，染色质信号转导和选择性基因控制的转录机制；（3）定义了HDACS与BET蛋白串扰的机制，以将上游信号与心脏中促性基因表达相结合。拟议的研究之所以重要，是因为它试图将药物赌注抑制抑制作用作为HF中的一种新型治疗策略，因此解决了巨大的未满足的临床需求。我们的建议具有很高的创新性，因为我们通过前所未有的方法成功地“药物”病理心肌转录和重塑。鉴于我们财团的协同专业知识，我们设想我们高度合业组的持续贡献将为开发新型心血管疾病的“表观遗传疗法”铺平道路。