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（由适用提供）：心力衰竭是美国和全球疾病和死亡的主要原因。该疾病的特征是心脏膨胀（肥大）和心脏僵硬（纤维化），这会导致心脏收缩和放松受损。首次接受心力衰竭后的五年死亡率> 40％，强调需要新的治疗策略。组蛋白脱乙酰基酶（HDAC）抑制剂已成为一种新的药物，这些药物已显示为减少心脏肥大并最终改善临床模型中心力衰竭。我们先前发表了HDAC抑制作用，通过上调核ERK1/2光光氨基酶，双特异性磷酸酶5（DUSP5）在心肌细胞中阻止核ERK1/2信号传导，从而阻止肥大。但是，关于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HF动物模型中病理心脏肥大的中心调节剂。在初步研究中，我们发布了DUSP5无效的小鼠会因核ERK磷酸化增强而产生夸张的心肥力，以应对压力。实际上，与野生型同窝仔相比，DUSP5缺陷型小鼠具有明显更大的左心室（LVS）以及增强的ERK1/2激活，以响应于 - 肾上腺素激动剂，异丙肾上腺素（ISO）的治疗。奇怪的是，ISO并未诱导野生型小鼠的RV肥大，而是触发了DUSP5无效小鼠RV质量增加约40％。这些数据表明DUSP5在控制RV肥大中起着重要作用。值得注意的是，相对于LV肥大，对控制病理RV生长的分子机制知之甚少。该应用将通过测试DUSP5通过去磷酸化的核ERK1/2作为符号依赖心脏肥大的反射剂的假设来填补关键空隙，而这种机制对于抑制RV肥大尤其重要。为了检验我们的假设，我们开发了两个具体的目标。 AIM 1将阐明HDAC使用染色质免疫沉淀（CHIP）和DNA甲基化技术来确定DUSP5启动子中表观遗传调节事件的机制。在AIM 2中，我们将解决DUSP5在控制心力衰竭动物模型中核ERK1/2磷酸化和病理RV肥大中的体内作用。拟议的研究将显着增加我们对RV增长的有限了解，并可能支持右侧心力衰竭患者的更好疗法的发展。