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

• 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
• 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

 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（由申请人提供）：尽管目前的标准治疗，心力衰竭（HF）的诊断与生活质量差和5年死亡率接近50%相关。鉴于这一迫切的未满足的需求，阐明HF发病机制中涉及的新机制有望为这种流行和致命的疾病确定新的治疗方法。本申请的PI首次说明了乙酰基-赖氨酸“阅读器”蛋白（BET布罗莫结构域）的保守家族在病理性心脏肥大和HF的转录控制中的关键作用。重要的是，这些研究利用了JQ 1的使用，JQ 1是BET溴结构域的一流的特异性小分子抑制剂。这种多PI应用旨在垂直推进我们对异常染色质依赖性信号转导（通过BET家族成员BRD 4）如何驱动病理性心脏重塑的理解。我们的长期目标是开发BET溴结构域抑制作为HF的新治疗策略。令人兴奋的初步研究表明，BRD 4介导的心肌细胞（CM）肥大在体外和BET抑制与JQ 1有力地抑制压力超负荷介导的心脏肥大在小鼠中的发展。从机制上讲，我们证明BRD 4占据了成年小鼠心脏中的活性增强子，将PTEF-b活性招募到转录起始位点，并触发RNA聚合酶II的暂停释放以激活对HF发病机制至关重要的基因。有趣的是，我们证明了病理应激导致CM中BRD 4蛋白的特异性积累，而Brd 4 mRNA没有任何增加。最后，我们证明了I类HDAC，这通常是促肥大的，是BRD 4蛋白积累所特别需要的。基于这一基本原理，该提议将测试中心假设，即BRD 4作为病理性心脏重塑的节点转录调节因子发挥作用，可以在体内靶向BRD 4。在强有力的初步数据的指导下，这一假设将通过追求三个强大的具体目标进行测试：（1）阐明BET抑制在临床相关的HF模型和生理心脏可塑性中的作用;（2）剖析BRD 4驱动动态增强子重塑、染色质依赖性信号转导和心脏应激期间选择性基因控制的转录机制;（3）确定HDAC与BET蛋白相互作用以整合上游信号与心脏中促肥大基因表达的机制。所提出的研究是重要的，因为其寻求开发药理学BET溴结构域抑制作为HF中的新型治疗策略，并且因此解决了巨大的未满足的临床需求。我们的建议是高度创新的，因为我们通过前所未有的方法成功地“药物”病理性心肌转录和重塑。鉴于我们联盟的协同专业知识，我们设想我们高度合作的小组的持续贡献将为心血管疾病的新型“表观遗传疗法”的开发铺平道路。