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）：尽管有当前的护理标准，心力衰竭 (HF) 的诊断仍与生活质量差和 5 年死亡率接近 50% 相关，鉴于这一迫切的未满足需求，需要进行澄清。心力衰竭发病机制中涉及的新机制的研究有望为这种流行且致命的疾病找到新的疗法。该应用的 PI 首次说明了乙酰赖氨酸“读取器”保守家族的关键作用。重要的是，这些研究利用了 JQ1，一种一流的 BET 溴结构域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 BRD4）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。令人兴奋的初步研究表明，BRD4 在体外介导心肌细胞 (CM) 肥大，并且 JQ1 的 BET 抑制可有效抑制小鼠压力超负荷介导的心脏肥大的发展。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，以激活对转录至关重要的基因有趣的是，我们证明病理应激导致 BRD4 蛋白在 CM 中特异性积累，而 Brd4 mRNA 没有任何增加。最后，我们证明 I 类 HDAC 通常是促肥大的，是 BRD4 蛋白积累所特别需要的。基于这一基本原理，该提案将测试以下中心假设：BRD4 作为病理性心脏重塑的节点转录调节因子，可以在强有力的初步数据的指导下在体内进行药理学靶向。该假设将通过追求三个强有力的具体目标来检验：(1) 阐明 BET 抑制在心力衰竭临床相关模型和生理心脏可塑性过程中的影响；(2) 剖析 BRD4 驱动动态增强子重塑、染色质的转录机制。 (3) 定义 HDAC 将与 BET 蛋白的串扰整合到心脏中促肥大基因表达的上游信号的机制。这项研究意义重大，因为它寻求开发药理学 BET 溴结构域抑制作为心力衰竭的一种新治疗策略，因此解决了巨大的未满足的临床需求，因为我们通过前所未有的方法成功地“药物”了病理性心肌转录和重塑。鉴于我们联盟的协同专业知识，我们预计，我们高度协作的团队的持续贡献将为开发心血管疾病的新型“表观遗传疗法”铺平道路。