Regulation of Cardiac Signaling by Class I Histone Deacetylases

I 类组蛋白脱乙酰酶对心脏信号传导的调节

基本信息

批准号：
8716810
负责人：
Timothy McKinsey
金额：
$ 37.98万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-08 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716810
关键词：
Address Admission activity Adult Agonist American Animal Model Biological Cardiac Cardiac Myocytes Catheters Clinic Data Depressed mood Development Economic Burden Enzymes Epigenetic Process Evaluation Event Excision Exhibits Fibrosis Foundations Gene Expression Genes Goals HDAC1 gene Health Healthcare Systems Heart Heart Hypertrophy Heart failure Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones Human In Vitro Lysine MAPK3 gene MEKs Measurement Mitogen-Activated Protein Kinases Nuclear Pathogenesis Patients Phosphoric Monoester Hydrolases Phosphotransferases Protein Isoforms Proteins Recruitment Activity Regulation Regulatory Element Research Rodent Model Role Signal Transduction Stress Therapeutic Thrombocytopenia Toxic effect Translating base cost derepression design drug discovery improved in vivo inhibitor/antagonist innovation insight mortality novel novel therapeutic intervention novel therapeutics public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of heart failure. With greater than five million heart failure patients in the U.S. alone, treatment of this conditio represents an estimated annual cost to the American health care system of over $37 billion. The 5-year mortality rate following first admission for heart failure is 42.3%, highlighting an urgent need for new therapeutic approaches. HDACs catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 HDACs are encoded by distinct genes. Broad-spectrum, 'pan'-HDAC inhibitors are efficacious in rodent models of heart failure, blocking pathological cardiac hypertrophy and fibrosis and improving cardiac function, suggesting an application for HDAC inhibitors for the treatment of human heart failure. However, since pan-HDAC inhibition is associated with toxicities such as thrombocytopenia, the potential for translating these findings to the heart failure clinic remains unclear. The current proposal is based on the overall hypothesis that class I HDACs contribute to the pathogenesis of heart failure by altering MAP kinase signaling in cardiac myocytes. As an extension of this hypothesis, we propose that selective inhibition of class I HDACs with small molecule inhibitors will provide a safe and effective therapeutic strategy for heart failure. Our preliminary data indicate that class I HDACs alter nuclear ERK1/2 signaling in cardiomyocytes by inducing expression of an ERK-specific phosphatase, DUSP5. Further studies will define the mechanisms for regulation of DUSP5 by class I HDACs, and the role of DUSP5 in the control of cardiac remodeling in vitro and in vivo. In vivo evaluation will include echocardiographic and catheter-based measurements of cardiac function as well as histological and morphometric assessment of cardiac hypertrophy and fibrosis. Together, results from these in vitro and in vivo studies will provide insights into signaling and transcriptional events controlling heart failure, and should provide the foundation for innovative approaches to drug discovery for heart failure based on isoform-selective HDAC inhibition.

描述（由申请人提供）：该项目的目标是解决组蛋白脱乙酰酶 (HDAC) 酶的子集（I 类 HDAC）在控制心力衰竭中的作用。仅在美国就有超过 500 万心力衰竭患者，治疗这种疾病意味着美国医疗保健系统每年的费用估计超过 370 亿美元。首次因心力衰竭入院后的 5 年死亡率为 42.3%，这凸显了对新治疗方法的迫切需要。 HDAC 催化去除多种蛋白质中赖氨酸残基上的乙酰基。 18 个 HDAC 由不同的基因编码。广谱“泛”HDAC 抑制剂在啮齿动物心力衰竭模型中有效，可阻止病理性心脏肥大和纤维化并改善心脏功能，这表明 HDAC 抑制剂可用于治疗人类心力衰竭。然而，由于泛 HDAC 抑制与血小板减少症等毒性相关，因此将这些发现转化为心力衰竭临床的潜力仍不清楚。目前的提议基于这样的总体假设：I 类 HDAC 通过改变心肌细胞中的 MAP 激酶信号传导来促进心力衰竭的发病机制。作为这一假设的延伸，我们提出用小分子抑制剂选择性抑制 I 类 HDAC 将为心力衰竭提供安全有效的治疗策略。我们的初步数据表明，I 类 HDAC 通过诱导 ERK 特异性磷酸酶 DUSP5 的表达来改变心肌细胞中的核 ERK1/2 信号传导。进一步的研究将明确 I 类 HDAC 调节 DUSP5 的机制，以及 DUSP5 在体外和体内控制心脏重塑中的作用。体内评估将包括心脏功能的超声心动图和基于导管的测量以及心脏肥大和纤维化的组织学和形态测量评估。总之，这些体外和体内研究的结果将为控制心力衰竭的信号传导和转录事件提供见解，并为基于异构体选择性 HDAC 抑制的心力衰竭药物发现创新方法奠定基础。