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。

基本信息

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
项目类别：
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

项目摘要

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.

项目概要心力衰竭（HF）是多种心血管疾病的最终临床表现，是一种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，其特征是细胞外基质过度沉积激活的心肌成纤维细胞产生的蛋白质，会降低组织顺应性并加速心力衰竭进展。染色质内核小体赖氨酸残基的乙酰化代表了一个重要的基因转录的表观遗传调控机制对心力衰竭发病机制至关重要。在特别是，乙酰赖氨酸阅读器蛋白 BRD4 因其重大贡献而受到认可促纤维化基因程序的转录以及心脏功能障碍的发展和改造。 BRD4 的功能研究表明，末端外 (ET) 结构域介导通过与辅因子蛋白相互作用实现促纤维化基因程序的转录延伸；然而，BRD4 ET 结构域抑制在治疗心血管疾病中的潜力尚待阐明。利用创新的肽抑制剂，拟议的研究将调查 BRD4 ET 结构域抑制对原代心脏成纤维细胞和小鼠模型的治疗潜力高频。第一个目标将测试以下假设：抑制 BRD4 的 ET 结构域将缓解原代小鼠和人心脏病理性肌成纤维细胞活化的特征成纤维细胞和染色质免疫沉淀测序将提供对成纤维细胞和染色质免疫沉淀测序的机制洞察这种抑制的潜在治疗特性。第二个目标将评估心脏保护作用这些新型 BRD4 ET 结构域抑制剂在临床相关压力过载模型中的特性高频。将评估对心脏功能障碍的潜在有益特性以及评估通过细胞外基质的组织学和蛋白质组学分析来研究肥大和纤维化重塑。最后，RNA测序将用于确定基因组中的全局基因表达变化。心肌对 BRD4 ET 结构域抑制的反应。重要的是，拟议的工作将显着提高申请人在原代细胞培养、心血管生理学、心力衰竭的啮齿动物模型，以及调节基因转录的表观遗传机制的研究。在心血管表观遗传学领域著名专家的指导下，致力于青年科学家的发展，本次培训将为申请者的未来发展打下坚实的基础。发展成为一名独立调查员。此外，这种创新方法还提供了令人兴奋的开发急需的治疗心力衰竭的新型治疗策略的潜力。