Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.

BRD4 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: 9975206
• 负责人: Timothy McKinsey
• 金额: $ 74.54万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975206
• 关键词: Address; Adult; Affect; Affinity; Area; Attenuated; BRD2 gene; Binding; Biology; Bromodomain; Cardiac; Cardiac Myocytes; Cells; ChIP-seq; Chemicals; Chromatin; Clinical; Clinical Data; Country; DNA Polymerase II; Data; Development; Diagnosis; Disease; Enhancers; Epigenetic Process; Evaluation; Family; Family member; Fibroblasts; Fibrosis; Funding; Genes; Genetic; Genetic Transcription; Goals; Health; Health Expenditures; Heart; Heart failure; Hospitalization; Human; In Vitro; Investigation; Knock-in Mouse; Knowledge; Left Ventricular Remodeling; Light; LoxP-flanked allele; Lysine; Mediating; Medical Research; Mission; Modeling; Molecular; Mus; Myofibroblast; National Heart, Lung, and Blood Institute; Nodal; Outcome; Pathogenesis; Pathologic; Patients; Peptides; Pharmacology; Population; Prodrugs; Protein Inhibition; Protein Isoforms; Proteins; Public Health; Qi; Quality of life; Rattus; Reader; Regulation; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic Effect; Time; Tissues; Transcriptional Regulation; United States; United States National Institutes of Health; base; cardiovascular disorder therapy; cell type; coronary fibrosis; disability; epigenetic therapy; epigenomics; gene discovery; heart function; improved; in vivo; inhibitor/antagonist; innovation; insight; mortality; mouse model; novel; novel therapeutics; periostin; programs; recruit; response; single-cell RNA sequencing; small molecule; small molecule inhibitor; standard of care; therapeutic target; tool; transcriptome sequencing; translational impact

Abstract 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 HF. Importantly, these studies leveraged the use of JQ1, a first-in-class, specific small molecule inhibitor of BET bromodomains. This multi-PI renewal application seeks to vertically advance our understanding of how aberrant chromatin-dependent signal transduction (via the BET family member BRD4) drives pathologic cardiac fibrosis. Our long-term objective is to develop BRD4 inhibition as a novel therapeutic strategy in HF. Exciting preliminary studies demonstrate that BRD4 mediates cardiac fibroblast activation in vitro, and that BRD4 inhibition with JQ1 suppresses cardiac fibrosis in mouse models of HF. Mechanistically, we demonstrate that BRD4 functions downstream of pro- fibrotic TGF- signaling by binding to regulatory enhancers that drive a gene program of myofibroblast (myoFB) activation. This proposal will test the central hypothesis that BRD4 functions as a nodal transcriptional regulator of pathological cardiac fibrosis that can be pharmacologically targeted in vivo. Guided by strong preliminary data, this hypothesis will be tested by pursuing three robust specific aims: (1) Discover the gene-specific role of BRD4 in cardiac myoFB in vivo; (2) Dissect the chromatin-dependent signaling mechanisms governing BRD4-dependent activation of endogenous cardiac myoFBs; (3) Define the roles of specific BRD4 functional domains in the control of cardiac myoFB activation. Several innovative tools that were developed during the first funding period will be employed to advance this new avenue of investigation, including floxed Brd4 mice, Brd4-3XFLAG knock-in mice, Brd4 bromodomain knock-in mice, as well as peptides and small molecules that selectively inhibit distinct functional domains in BRD4. The proposed research is significant because it will facilitate development of pharmacologic BRD4 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” pro-fibrotic transcription and remodeling via unprecedented approaches, we define the functions of BRD4 in cardiac fibroblasts for the first time, and we provide the first epigenomic evaluation of cardiac fibroblasts. 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.

抽象的 尽管当前的护理标准，但心力衰竭（HF）的诊断与生活质量差有关 5年死亡率接近50％。鉴于这种紧急未满足的需求，阐明了新机制 参与HF发病机理有望鉴定这种流行和致命疾病的新疗法。 该应用的PI是第一个说明保守乙酰赖氨酸家族至关重要的作用的PI HF转录控制中的“读取器”蛋白（BET溴化群）。重要的是，这些研究 利用JQ1的使用，JQ1是BET溴结构域的第一类，特定的小分子抑制剂。这个多pi 更新应用旨在垂直提高我们对异常染色质信号的理解 转导（通过BET家族成员BRD4）驱动病理心脏纤维化。我们的长期目标是 将BRD4抑制作为HF中的一种新型治疗策略。令人兴奋的初步研究表明 BRD4在体外介导心脏成纤维细胞激活，而BRD4抑制JQ1抑制心脏 HF小鼠模型中的纤维化。从机械上讲，我们证明了BRD4在Pro-下游的功能 通过与驱动肌纤维细胞基因程序的调节增强剂结合来结合纤维化TGF-信号传导 （MyOFB）激活。该提案将检验中心假设，即BRD4起淋巴结功能 病理心脏纤维化的转录调节剂，可以在体内靶向药物。指导 通过强大的初步数据，将通过追求三个强大的特定目的来检验该假设：（1）发现 BRD4在体内心脏MyOFB中的基因特异性作用； （2）剖析染色质依赖性信号传导 依赖内源性心脏肌动物的BRD4依赖激活的机制； （3）定义 心脏MyOFB激活控制中的特定BRD4功能域。几种创新工具 在第一个资金期间开发的将聘请以推进这一新的调查途径， 包括Floxed Brd4小鼠，BRD4-3XFLAG敲入小鼠，BRD4溴化域敲入小鼠，以及 肽和小分子有选择地抑制BRD4中不同功能结构域。提议 研究之所以重要，是因为它将促进制药Cologic BRD4抑制作用作为一种新颖 HF中的治疗策略，因此解决了巨大的未满足临床需求。我们的建议很高 创新性，因为我们成功地通过前所未有的“药物”促纤维化转录和重塑 方法是，我们首次定义BRD4在心脏成纤维细胞中的功能，我们提供了第一个 心脏成纤维细胞的表观基因组学评估。鉴于我们财团的协同专业知识，我们设想 我们高度合并的小组的持续贡献将为发展新颖的道路铺平道路 心血管疾病的“表观遗传疗法”。