p38 acetylation: Novel signaling mechanisms and myocardial protection

p38 乙酰化：新的信号传导机制和心肌保护

• 批准号: 8826803
• 负责人: TING C ZHao
• 金额: $ 42.26万
• 依托单位: ROGER WILLIAMS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826803
• 关键词: Acetylation; Adenovirus Infections; Animal Model; Attenuated; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cessation of life; Complex; Deacetylation; Development; Diagnosis; Disease; Dominant-Negative Mutation; Event; Family suidae; HDAC4 gene; Health; Heart; Histones; Human; Hypoxia; In Vitro; Injury; Ischemia; Lead; Life; Lysine; MAPK14 gene; Mediating; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Organ; Patients; Phosphorylation; Physiological; Regulation; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Time; United States; Ventricular Function; Work; base; clinically relevant; design; human MAPK14 protein; human subject; improved; in vivo Model; innovation; insight; interdisciplinary approach; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; protective effect; protein expression; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of deaths among patients in the world today. Discovering novel mechanisms during ischemia and developing efficacious and clinically relevant therapeutic strategies hold promise in the treatment of the ischemic heart. The latest emerging evidence suggests that among the leading mechanistic approaches in mediating myocardial ischemic injury is acetylation/deacetylation. Our recent focused works have demonstrated that inhibition of histone deacetylases (HDAC) leads to a profound cardioprotection, which is closely associated with p38 mitogen-activated protein kinase. p38 is one of the most important mechanisms in regulation of myocardial ischemic injury, development, and hypertrophic response. By using interdisciplinary approaches, our innovative discovery recently documented that p38 is subject to regulation by acetylation. We have identified that p38 is acetylated at lysines 15, 53, and 121 amino residues, respectively. The intriguing preliminary study and established works from our lab strongly support a functional role for p38 acetylation in protecting the heart against ischemic injury. However, the physiological function and molecular mechanism by which acetylation of p38 mediates cardiac injury and protection remain unknown. These exciting and novel findings lead to our current hypothesis that p38 acetylation is a signaling mechanism critical for myocardial protection and regulation of downstream substrate HDAC4 to form a partnership in the genesis of protective events. The specific aims of our proposed studies are the following: Specific Aim 1: Determine if p38 acetylation is essential for cardiomyocytes to survive against hypoxia in vitro. Specific Aim 2: Elucidate the physiological role of p38 acetylation in mediating myocardial injury and cardiac remodeling. Specific Aim 3: Investigate the role of p38 acetylation-mediated HDAC4 inactivation in the regulation of cardioprotection. Specific Aim 4: Use a preclinical large animal model to examine the role of p38 acetylation in HDAC inhibition-induced myocardial protection. Taken together, the proposed aims will for the first time establish that activation of p38 acetylation associated with HDAC4 inactivation prevents myocardial injury. All of these studies will not only uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will also have great potential to develop a new therapeutic approach to improve human health.

描述（由申请人提供）：缺血性心脏病是当今世界患者死亡的主要原因。发现缺血期间的新机制并制定有效且临床相关的治疗策略有望治疗缺血性心脏。最新出现的证据表明，介导心肌缺血性损伤的主要机制方法之一是乙酰化/脱乙酰化。我们最近的重点工作表明，抑制组蛋白脱乙酰酶 (HDAC) 可产生深远的心脏保护作用，这与 p38 丝裂原激活蛋白激酶密切相关。 p38 是调节心肌缺血损伤、发育和肥厚反应的最重要机制之一。通过使用跨学科方法，我们的创新发现最近证明 p38 受到乙酰化的调节。我们已经确定 p38 分别在赖氨酸 15、53 和 121 氨基酸残基处被乙酰化。我们实验室有趣的初步研究和已建立的工作有力地支持了 p38 乙酰化在保护心脏免受缺血性损伤中的功能作用。然而，p38乙酰化介导心脏损伤和保护的生理功能和分子机制仍不清楚。这些令人兴奋的新颖发现导致我们目前的假设：p38 乙酰化是一种信号传导机制，对于心肌保护和下游底物 HDAC4 的调节至关重要，以在保护事件的发生中形成伙伴关系。我们提出的研究的具体目标如下： 具体目标 1：确定 p38 乙酰化是否对于心肌细胞在体外缺氧下生存至关重要。具体目标 2：阐明 p38 乙酰化在介导心肌损伤和心脏重塑中的生理作用。具体目标 3：研究 p38 乙酰化介导的 HDAC4 失活在心脏保护调节中的作用。具体目标 4：使用临床前大型动物模型检查 p38 乙酰化在 HDAC 抑制诱导的心肌保护中的作用。总而言之，所提出的目标将首次确定与 HDAC4 失活相关的 p38 乙酰化激活可预防心肌损伤。所有这些研究不仅将揭示细胞信号传导和心肌保护方面的新颖且令人兴奋的机制，而且还将具有开发改善人类健康的新治疗方法的巨大潜力。