Exploring the Therapeutic Potential of BRD4 Extra-terminal Domain Inhibition in Cardiac Dysfunction and Remodeling. Fellow: Joshua Travers

探索 BRD4 末端结构域抑制对心脏功能障碍和重构的治疗潜力。

• 批准号: 9758647
• 负责人: Joshua Travers
• 金额: $ 6.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2021-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758647
• 关键词: Acetylation; Attenuated; Bromodomain; Cardiac; Cardiac development; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Proliferation; ChIP-seq; Characteristics; Chromatin; Clinical; Dependovirus; Deposition; Development; Disease; Echocardiography; Epigenetic Process; Etiology; Evaluation; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gene Expression; Gene Expression Alteration; Gene Expression Profiling; Genes; Genetic Transcription; Heart failure; Histology; Histones; Human; Hypertrophy; Investigation; Laboratories; Lysine; Mass Spectrum Analysis; Mediating; Mentorship; Modeling; Molecular; Mus; Myocardial; Myocardial dysfunction; Myocardium; Myofibroblast; Outcome; Pathogenesis; Pathologic; Peptides; Primary Cell Cultures; Property; Proteins; Proteomics; Reader; Regulator Genes; Research Personnel; Rodent Model; Role; Scientist; Signal Transduction; Solid; Surgical Models; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transcription Elongation; Treatment Efficacy; Ventricular; Ventricular Remodeling; Work; cardioprotection; clinically relevant; constriction; hemodynamics; inhibitor/antagonist; innovation; insight; interstitial; mouse model; novel; novel therapeutics; outcome forecast; pressure; programs; protective effect; response; skills; small molecule inhibitor; transcriptome; transcriptome sequencing; treatment strategy

Project Summary Heart failure (HF), the final clinical manifestation of numerous cardiovascular pathologies, is a devastating disease with poor prognosis. Nearly all etiologies of cardiovascular disease involve pathological myocardial remodeling, characterized by excessive deposition of extracellular matrix proteins by activated cardiac myofibroblasts, which reduces tissue compliance and accelerates HF progression. Acetylation of nucleosomal lysine residues within chromatin represents an important epigenetic regulatory mechanism of gene transcription that is critical to HF pathogenesis. In particular, the acetyl-lysine reader protein BRD4 has been recognized for its significant contributions to the transcription of pro-fibrotic gene programs, along with the development of cardiac dysfunction and remodeling. Functional studies of BRD4 indicate that the extra-terminal (ET) domain mediates transcriptional elongation of pro-fibrotic gene programs via interactions with co-factor proteins; however, the potential for BRD4 ET domain inhibition in the treatment of cardiovascular disease has yet to be elucidated. Utilizing innovative peptide inhibitors, the proposed studies will investigate the therapeutic potential of BRD4 ET domain inhibition in primary cardiac fibroblasts and a murine model of HF. The first aim will test the hypothesis that inhibition of the ET domain of BRD4 will alleviate characteristics of pathological myofibroblast activation in primary mouse and human cardiac fibroblasts, and chromatin immunoprecipitation sequencing will provide mechanistic insight into the potential therapeutic properties of this inhibition. The second aim will evaluate the cardioprotective properties of these novel BRD4 ET domain inhibitors in a clinically relevant pressure-overload model of HF. Potential salutary properties on cardiac dysfunction will be assessed, along with the evaluation of hypertrophy and fibrotic remodeling by histology and proteomic analysis of the extracellular matrix. Finally, RNA-sequencing will be utilized to determine global gene expression alterations in the myocardium in response to BRD4 ET domain inhibition. Importantly, the proposed work will significantly enhance the applicant's skill sets in primary cell culture, cardiovascular physiology, rodent models of HF, and the investigation of epigenetic mechanisms regulating gene transcription. Together with the mentorship of a renowned expert in cardiovascular epigenetics committed to the development of young scientists, this training will provide a solid foundation for the applicant's development into an independent investigator. Moreover, this innovative approach offers the exciting potential for the development of direly needed novel therapeutic strategies for the treatment of HF.

项目摘要 心力衰竭（HF）是许多心血管疾病的最终临床表现，是一种严重的心血管疾病。 预后不良的毁灭性疾病。几乎所有心血管疾病的病因都涉及 病理性心肌重塑，以细胞外基质过度沉积为特征 激活的心肌成纤维细胞释放蛋白质，降低组织顺应性，加速HF 进展染色质内核小体赖氨酸残基的乙酰化是一个重要的 基因转录的表观遗传调节机制，对HF发病机制至关重要。在 特别是，乙酰赖氨酸阅读蛋白BRD 4已被公认为其重要贡献 沿着心功能不全的发生， 和重塑。BRD 4的功能研究表明，末端外（ET）结构域介导了BRD 4的功能。 通过与辅因子蛋白相互作用的促纤维化基因程序的转录延伸; 然而，BRD 4 ET结构域抑制在心血管疾病治疗中的潜力， 尚未阐明。利用创新的肽抑制剂，拟议的研究将调查 BRD 4 ET结构域抑制在原代心脏成纤维细胞和鼠模型中的治疗潜力 的HF。第一个目的是检验抑制BRD 4的ET结构域将减轻 小鼠和人原代心肌病理性肌成纤维细胞活化的特点 成纤维细胞，染色质免疫沉淀测序将提供机制的见解， 这种抑制的潜在治疗特性。第二个目标是评估心脏保护作用， 这些新型BRD 4 ET结构域抑制剂在临床相关压力超负荷模型中的性质 的HF。将沿着评价对心功能不全的潜在有益特性 通过细胞外基质的组织学和蛋白质组学分析， 最后，将利用RNA测序来确定基因表达的总体变化。 心肌对BRD 4 ET结构域抑制的响应。重要的是，拟议的工作将 显著提高申请人在原代细胞培养，心血管生理学， 啮齿类动物HF模型，以及调节基因转录的表观遗传机制的研究。 再加上一位心血管表观遗传学著名专家的指导， 青年科学家的发展，这种培训将提供一个坚实的基础，申请人的 发展成为独立调查员。此外，这种创新的方法提供了令人兴奋的 开发迫切需要的治疗HF的新治疗策略的潜力。