Regulation of Cardiac Signaling by Class I Histone Deacetylases

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)的一个子集，即I类HDAC在心力衰竭控制中的作用。仅在美国就有500多万心力衰竭患者，这种疾病的治疗每年给美国医疗保健系统带来的成本估计超过370亿美元。因心力衰竭首次入院后的5年死亡率为42.3%，凸显了对新的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中的乙酰基。这18个HDAC由不同的基因编码。广谱的‘PAN’-HDAC抑制剂在心力衰竭的啮齿动物模型中是有效的，可以阻断病理性心肌肥大和纤维化，改善心功能，提示HDAC抑制剂在治疗人类心力衰竭方面的应用。然而，由于PAN-HDAC抑制与血小板减少等毒性反应有关，将这些发现转化为心力衰竭临床的可能性尚不清楚。目前的建议是基于这样的总体假设，即I类HDAC通过改变心肌细胞中的MAP激酶信号而参与心力衰竭的发病机制。作为这一假设的延伸，我们认为，用小分子抑制剂选择性抑制I类HDAC将为心力衰竭提供一种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的核ERK1/2信号转导。进一步的研究将确定I类HDAC调节DUSP5的机制，以及DUSP5在体外和体内控制心脏重构中的作用。体内评估将包括超声心动图和基于导管的心功能测量，以及心肌肥大和纤维化的组织学和形态计量学评估。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和转录事件提供洞察力，并将为基于异构体选择性HDAC抑制的心力衰竭药物开发的创新方法提供基础。

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.