Role of dual-specificity phosphatase 5 (DUSP5) in the regulation of right ventric

双特异性磷酸酶 5 (DUSP5) 在右心室调节中的作用

• 批准号: 8783023
• 负责人: Bradley S Ferguson
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783023
• 关键词: Acute; Address; Admission activity; Adrenergic Agonists; Adult; Animal Model; Binding; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiovascular system; Cell Death; Cessation of life; Chronic; Complex; DNA Methylation; Data; Development; Disease; Epigenetic Process; Event; Exhibits; Failure; Fibrosis; Gene Expression; Genes; Genetic Transcription; Goals; Growth; HDAC3 gene; Heart; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Hypertension; Hypertrophy; Hypoxia; Isoproterenol; Knockout Mice; Knowledge; Left ventricular structure; Mitogen-Activated Protein Kinases; Modification; Molecular; Mus; Myocardial Contraction; Myocardial Infarction; Nuclear; Outcome; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Pre-Clinical Model; Protein Isoforms; Publishing; Regulation; Relative (related person); Relaxation; Right Ventricular Hypertrophy; Role; Side; Signal Transduction; Specificity; Stimulus; Stress; Techniques; Testing; Ventricular; Wild Type Mouse; Work; base; chromatin immunoprecipitation; improved; in vivo; novel; novel therapeutics; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Heart failure is a major cause of disease and death in the US and worldwide. Features of this disease are heart enlargement (hypertrophy) and heart stiffness (fibrosis), which result in impaired heart contraction and relaxation. The five-year deat rate following first admission of heart failure is >40%, stressing the need for new therapeutic strategies. Histone deacetylase (HDAC) inhibitors have emerged as a new class of drugs that have been shown as effective in reducing cardiac hypertrophy and ultimately improving heart failure in pre- clinical models. We previously published that HDAC inhibition blocks nuclear ERK1/2 signaling, and thus hypertrophy, by upregulating the nuclear ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5) in cardiac myocytes. However, nothing is known about the in vivo function of DUSP5 in the heart. Recent studies demonstrate that nuclear ERK1/2 signaling is a central regulator of pathological cardiac hypertrophy in animal models of HF. In preliminary studies, we postulated that DUSP5 null mice would develop exaggerated cardiac hypertrophy in response to stress due to enhanced nuclear ERK phosphorylation. Indeed, DUSP5-deficient mice had significantly larger left ventricles (LVs), as well as enhanced ERK1/2 activation, compared to wild- type littermates in response to treatment with the ¿-adrenergic agonist, isoproterenol (ISO). Curiously, ISO did not induce RV hypertrophy in wild-type mice, but triggered a ~40% increase in RV mass in DUSP5 null mice. These data suggest a prominent role for DUSP5 in the control of RV hypertrophy. Significantly, relative to LV hypertrophy, little is known about the molecular mechanisms controlling pathological RV growth. This application will fill a critical void by testing the hypothesis that DUSP5 functions as a signl-dependent repressor of cardiac hypertrophy by dephosphorylating nuclear ERK1/2, and this mechanism is especially critical for suppression of RV hypertrophy. To test our hypothesis, we have developed two specific aims. Aim 1 will elucidate the mechanism(s) by which HDACs control DUSP5 expression in cardiac myocytes using chromatin immunoprecipitation (ChIP) and DNA methylation techniques to determine epigenetic regulatory events within the dusp5 promoter. In Aim 2, we will address the in vivo role ofDUSP5 in the control of nuclear ERK1/2 phosphorylation and pathological RV hypertrophy in animal models of heart failure. The proposed study will significantly add to our limited knowledge regarding RV growth, potentially facilitating development of better therapies for patients with right-sided heart failure.

描述（由申请人提供）：心力衰竭是美国和全世界疾病和死亡的主要原因。这种疾病的特征是心脏增大（肥大）和心脏僵硬（纤维化），导致心脏收缩和舒张受损。首次入院心力衰竭后的年死亡率> 40%，这凸显了对新治疗策略的需求，组蛋白脱乙酰酶 (HDAC) 抑制剂已成为一种已被证明在治疗中有效的新型药物。减少心脏肥大并最终改善临床前模型中的心力衰竭 我们之前发表了HDAC抑制通过上调心脏中的核ERK1/2磷酸酶、双特异性磷酸酶5 (DUSP5)来阻断核ERK1/2信号传导，从而阻断肥厚。然而，人们对 DUSP5 在心脏中的体内功能一无所知。最近的研究表明，核 ERK1/2 信号传导是病理学的核心调节因子。心力衰竭动物模型中的心脏肥大。在初步研究中，我们假设由于核 ERK 磷酸化增强，DUSP5 缺失小鼠会出现过度的心脏肥大，事实上，DUSP5 缺陷小鼠的左心室 (LV) 明显更大。与野生型同窝动物相比，ERK1/2 激活增强，对 ¿奇怪的是，ISO 不会诱导野生型小鼠的 RV 肥大，但会引发 DUSP5 缺失小鼠的 RV 质量增加约 40%。这些数据表明 DUSP5 在控制 RV 中发挥着重要作用。值得注意的是，相对于左心室肥大，人们对控制病理性右心室生长的分子机制知之甚少，该应用将通过测试 DUSP5 的假设来填补一个关键空白。通过使核 ERK1/2 去磷酸化，发挥信号依赖性心脏肥大抑制因子的作用，并且这种机制对于抑制 RV 肥大尤其重要。为了检验我们的假设，我们制定了两个具体目标，以阐明该机制。 In Aim 中，HDAC 使用染色质免疫沉淀 (ChIP) 和 DNA 甲基化技术控制心肌细胞中的 DUSP5 表达，以确定 dusp5 启动子内的表观遗传调控事件。 2，我们将探讨DUSP5在心力衰竭动物模型中控制核ERK1/2磷酸化和病理性RV肥大中的作用。拟议的研究将显着增加我们关于RV生长的有限知识，有可能促进更好的治疗方法的开发。适用于右心衰竭患者。