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

• 批准号: 8577925
• 负责人: Timothy McKinsey
• 金额: $ 36.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/8577925
• 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

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）：本项目的目标是解决组蛋白脱乙酰酶（HDAC）酶的一个子集（I类HDAC）在心力衰竭控制中的作用。仅在美国就有超过500万的心力衰竭患者，治疗这种疾病对美国卫生保健系统来说估计每年的费用超过370亿美元。首次因心力衰竭入院后的5年死亡率为42.3%，这突出表明迫切需要新的治疗方法。HDAC催化从多种蛋白质中的赖氨酸残基去除乙酰基。18种HDAC由不同的基因编码。广谱"泛“-HDAC抑制剂在心力衰竭的啮齿动物模型中有效，阻断病理性心脏肥大和纤维化并改善心脏功能，表明HDAC抑制剂用于治疗人心力衰竭的应用。然而，由于泛HDAC抑制与毒性（如血小板减少症）相关，因此将这些发现转化为心力衰竭临床的可能性仍不清楚。目前的建议是基于总体假设，即I类HDAC通过改变心肌细胞中的MAP激酶信号传导而促成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DUSP 5的表达来改变心肌细胞中的核ERK 1/2信号传导。进一步的研究将确定I类HDAC调节DUSP 5的机制，以及DUSP 5在体外和体内控制心脏重塑中的作用。体内评价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学评估。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，并应为基于异构体选择性HDAC抑制的心力衰竭药物发现的创新方法提供基础。