Regulation of Cardiac Signaling by Class I Histone Deacetylases

描述（由申请人提供）：该项目的目标是解决组蛋白去乙酰化酶（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，据估计，美国医疗保健系统每年的治疗费用超过370亿美元。心力衰竭首次入院后的5年死亡率为42.3%，这表明迫切需要新的治疗方法。hdac可以催化多种蛋白质中赖氨酸残基的乙酰基去除。18种hdac由不同的基因编码。广谱泛型HDAC抑制剂在啮齿类动物心力衰竭模型中有效，阻断病理性心脏肥大和纤维化，改善心功能，提示HDAC抑制剂在人类心力衰竭治疗中的应用。然而，由于泛hdac抑制与血小板减少等毒性有关，因此将这些发现转化为心力衰竭临床的潜力仍不清楚。目前的建议是基于I类hdac通过改变心肌细胞中MAP激酶信号通路参与心力衰竭发病机制的总体假设。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中的核ERK1/2信号。进一步的研究将明确I类hdac调控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和转录事件提供见解，并为基于同种异构体选择性HDAC抑制的心力衰竭药物发现的创新方法提供基础。

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.