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球疾病和死亡的主要原因。这种疾病的特征是心脏扩大（肥大）和心脏僵硬（纤维化），导致心脏收缩和舒张受损。心力衰竭首次入院后的5年死亡率> 40%，强调需要新的治疗策略。组蛋白去乙酰化酶（HDAC）抑制剂已经作为一类新的药物出现，其已经在临床前模型中显示出有效减少心脏肥大并最终改善心力衰竭。我们先前发表了HDAC抑制通过上调心肌细胞核ERK 1/2磷酸酶，双特异性磷酸酶5（DUSP 5）阻断核ERK 1/2信号传导，从而阻断心肌肥大。然而，对DUSP 5在心脏中的体内功能一无所知。最近的研究表明，核ERK 1/2信号转导是HF动物模型中病理性心脏肥大的中心调节因子。在初步研究中，我们假设DUSP 5基因敲除小鼠由于核ERK磷酸化的增强，在应激反应中会发生过度的心脏肥大。事实上，与野生型同窝小鼠相比，DUSP 5缺陷小鼠具有显著更大的左心室（LV），以及增强的ERK 1/2活化，以响应用β-肾上腺素能激动剂异丙肾上腺素（ISO）处理。奇怪的是，ISO并没有诱导野生型小鼠的RV肥大，但引发了DUSP 5缺失小鼠的RV质量增加约40%。这些数据表明DUSP 5在控制RV肥大中的突出作用。值得注意的是，相对于LV肥大，对控制病理性RV生长的分子机制知之甚少。该申请将通过测试DUSP 5通过去磷酸化核ERK 1/2作为心脏肥大的信号依赖性抑制剂发挥作用的假设来填补关键空白，并且该机制对于抑制RV肥大尤其关键。为了验证我们的假设，我们制定了两个具体目标。目的1将阐明HDAC控制心肌细胞中DUSP 5表达的机制，使用染色质免疫沉淀（ChIP）和DNA甲基化技术来确定dusp 5启动子内的表观遗传调控事件。在目标2中，我们将探讨DUSP 5在心力衰竭动物模型中控制核ERK 1/2磷酸化和病理性RV肥大的体内作用。这项拟议的研究将显著增加我们对右心室生长的有限了解，可能有助于为右侧心力衰竭患者开发更好的治疗方法。