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。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的尽管有当前的护理标准，心力衰竭 (HF) 的诊断仍与生活质量差和心脏衰竭有关。 5 年死亡率接近 50% 鉴于这一迫切的未满足需求，需要阐明新的机制。心力衰竭发病机制的参与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保守家族的关键作用重要的是，这些研究表明 HF 转录控制中的“阅读器”蛋白（BET 溴结构域）。利用 JQ1，一种一流的 BET 溴结构域特异性小分子抑制剂，这种多 PI。更新应用旨在垂直推进我们对异常染色质依赖性信号如何产生的理解转导（通过 BET 家族成员 BRD4）驱动病理性心脏纤维化我们的长期目标是。开发 BRD4 抑制作为心力衰竭的新型治疗策略。 BRD4 在体外介导心脏成纤维细胞活化，并且 JQ1 抑制 BRD4 可抑制心脏成纤维细胞活化心力衰竭小鼠模型中的纤维化从机制上讲，我们证明 BRD4 在 pro-下游发挥作用。通过与驱动肌成纤维细胞基因程序的调节增强子结合来调节纤维化 TGF-β 信号传导 (myoFB) 激活该提案将测试 BRD4 作为节点的中心假设。病理性心脏纤维化的转录调节因子，可在体内进行药理学靶向。通过强有力的初步数据，该假设将通过追求三个强有力的具体目标来检验：（1）发现 BRD4 在体内心脏 myoFB 中的基因特异性作用；（2）解析染色质依赖性信号传导；控制 BRD4 依赖性内源性心肌肌FB 激活的机制 (3) 定义以下作用：控制心脏 myoFB 激活的特定 BRD4 功能域是几种创新工具。在第一个资助期间开发的将用于推进这一新的调查途径，包括 floxed Brd4 小鼠、Brd4-3XFLAG 敲入小鼠、Brd4 bromodomain 敲入小鼠以及选择性抑制 BRD4 中不同功能域的肽和小分子。研究意义重大，因为它将促进药理学 BRD4 抑制作为一种新型药物的开发心力衰竭的治疗策略，因此解决了巨大的未满足的临床需求。创新是因为我们通过前所未有的方式成功地“药物”促纤维化转录和重塑方法，我们首次定义了 BRD4 在心脏成纤维细胞中的功能，并且我们提供了第一个鉴于我们联盟的协同专业知识，我们设想对心脏成纤维细胞进行表观基因组评估。我们高度协作的团队的持续贡献将为小说的发展铺平道路心血管疾病的“表观遗传疗法”。