The role of BET proteins in pathological cardiac remodeling

BET蛋白在病理性心脏重塑中的作用

基本信息

批准号：
10538142
负责人：
Ashley Francois
金额：
$ 4.2万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538142
关键词：
Adult Agonist American Angiotensin II Antibodies Apoptosis Architecture BRD2 gene Binding Biological Assay Bromodomain Cardiac Cardiac Myocytes Caspase Cell Culture Techniques Cells Cessation of life ChIP-seq Chemicals Chromatin Chronic Clinical Coupled DNA Polymerase II Deposition Disease Disease Progression Echocardiography Electric Conductivity Enhancers Epigenetic Process Extracellular Matrix Extracellular Matrix Proteins Family Family member Fibroblasts Fibrosis Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genome Goals Heart Heart Hypertrophy Heart failure Histology Histones Homeostasis Hypertrophy Immunoprecipitation Impairment Individual Inflammation Infusion procedures Injury Investigation Laboratories Left ventricular structure Lysine Measures Mediating Methods Mitochondria Mus Muscle Cells Myocardial dysfunction Myofibroblast Norepinephrine Pathologic Pathology Patient-Focused Outcomes Patients Pharmacology Phenylephrine Physiology Prevention Process Protein Family Proteins RNA Rattus Reader Relaxation Rodent Model Role Stimulus Stress Supervision Tamoxifen Tertiary Protein Structure Testing Tissues Ventricular Work adverse outcome base cell type chromatin protein coronary fibrosis effective therapy epigenetic regulation experimental study heart function heart preservation hemodynamics improved in vivo in vivo evaluation inhibitor insight mimetics mouse model programs promoter response small molecule small molecule inhibitor targeted treatment therapeutically effective wound healing wound response

项目摘要

ABSTRACT In response to persistent neurohormonal/hemodynamic stress or injury, the heart undergoes a pathologic remodeling process typically characterized by cardiomyocyte hypertrophy and fibrosis. Cardiac fibrosis, defined as excess extracellular matrix deposition in the heart, is a major contributor to both systolic and diastolic dysfunction for millions of heart failure patients. Upon injury, resident quiescent fibroblasts undergo a cell state transition to become activated fibroblasts and myofibroblasts that hyper-secrete extracellular matrix proteins and can be contractile. Fibrotic remodeling causes stiffening of the left ventricle, impaired relaxation, reduced compliance, and altered electrical conductance. This drives disease progression and worsens pathology. Despite the well-known contribution of cardiac fibrosis to adverse outcomes associated with heart failure, effective therapies targeting fibrosis in the heart remain elusive. Inhibition of the BET (bromodomain and extra-terminal domain) family of epigenetic reader proteins with chemical small molecules (e.g. JQ1) has proven effective at blocking in vivo cardiac hypertrophy, inflammation, and fibrosis and preserving cardiac function in rodent models of heart failure. Though these inhibitors block all BET proteins in the heart (BRD2, BRD3, BRD4), genetic targeting of individual BET proteins in cell culture experiments support the notion that BRD4 is the main BET protein responsible for activation of pathologic gene expression programs in cardiomyocytes and cardiac fibroblasts. However, recent work has given insight on the cell-type specific role of BRD4 in cardiomyocytes, uncovering an essential role for BRD4 in maintaining mitochondrial homeostasis. Conditional deletion of BRD4 in adult cardiomyocytes resulted in progressive cardiac dysfunction, impaired mitochondrial function, and eventual death in mice. Taken together with previous studies, this suggests that the beneficial effects of small molecule BET inhibitors in mouse models of heart failure are unlikely to be mediated exclusively by inhibition of BRD4 in cardiomyocytes. We hypothesize that genetic in vivo disruption of BRD4 in activated fibroblasts will safely block fibrosis and that multiple BET proteins (i.e. also BRD2 and BRD3) mediate the beneficial effects of small-molecule pan-BET inhibition. In Aim 1, we will determine the in vivo role of BRD4 in activated fibroblasts, and in Aim 2 we will elucidate the previously unexplored role of individual BET proteins in cardiac cell gene expression regulation through ChIP-Seq. This work will be carried out in the laboratory of Dr. Matthew Stratton, an expert in epigenetic regulation of pathologic cardiac remodeling, and under the co-supervision of Dr. Loren Wold, a world-leader in cardiac physiology. Our long-term goal is to develop safe and effective therapeutics to improve clinical outcomes for patients with cardiac fibrosis and HF.

抽象的响应持续性神经激素/血液动力学应激或损伤，心脏经历病理通常以心肌细胞肥大和纤维化为特征的重塑过程。心脏纤维化，定义为心脏中过多的细胞外基质沉积，是收缩期和数百万心力衰竭患者的舒张功能障碍。受伤后，居民静止的成纤维细胞经历细胞态转变，成为活化的成纤维细胞和肌纤维细胞，这些细胞外基质蛋白质，可以是收缩的。纤维化重塑会导致左心室变硬，放松受损，降低了依从性，并改变了电导。这推动了疾病的进展并恶化病理。尽管心脏纤维化对与心脏相关的不良后果的贡献众所周知失败，靶向心脏纤维化的有效疗法仍然难以捉摸。抑制BET（溴结构域和末端结构域）具有化学小分子（例如JQ1）的表观遗传学读蛋白家族（例如JQ1）被证明有效地阻断体内心脏肥大，炎症和纤维化并保留心脏在心力衰竭的啮齿动物模型中的功能。尽管这些抑制剂阻止了心脏中所有BET蛋白（BRD2， BRD3，BRD4），在细胞培养实验中单个BET蛋白的遗传靶向支持以下概念 BRD4是负责激活病理基因表达程序的主要BET蛋白心肌细胞和心脏成纤维细胞。但是，最近的工作已经深入了解了细胞类型的特定作用 BRD4在心肌细胞中，发现BRD4在维持线粒体稳态中的重要作用。成人心肌细胞中BRD4的有条件缺失导致心脏功能障碍，受损线粒体功能，最终在小鼠中死亡。与以前的研究一起，这表明在心力衰竭的小鼠模型中，小分子下注抑制剂的有益作用不太可能介导仅通过抑制心肌细胞中BRD4的抑制。我们假设Brd4在体内破坏了遗传活化的成纤维细胞将安全阻塞纤维化，并且多种BET蛋白（即BRD2和BRD3）介导小分子泛膏抑制的有益作用。在AIM 1中，我们将确定体内角色活化成纤维细胞中的Brd4的of，在AIM 2中，我们将阐明个人先前未开发的作用通过CHIP-SEQ调节心脏细胞基因表达调节中的BET蛋白。这项工作将在马修·斯特拉顿（Matthew Stratton）博士的实验室。在心脏生理学世界领导者洛伦·沃尔德（Loren Wold）博士的共同审视下。我们的长期目标是开发安全有效的治疗剂，以改善心脏纤维化和HF患者的临床结果。