REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

HIPPO 通路对心肌生长和死亡的调节

• 批准号: 8764135
• 负责人: Junichi Sadoshima
• 金额: $ 7.95万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764135
• 关键词: Acute; Address; Apoptosis; Area; Attenuated; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cell Death Signaling Process; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Complex; Cytokine Suppression; Development; Drosophila genus; Evolution; Fibroblasts; Functional disorder; Genetic; Genetic Transcription; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Homologous Gene; Hypertrophy; Injury; Ischemia; Knowledge; Lead; Mammals; Mediating; Mediator of activation protein; Medical; Mitochondria; Mitochondrial Proteins; Myocardial; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Nuclear; Organ Size; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Series; Signal Pathway; Signal Transduction; Sterility; Stress; TNF gene; cell type; cytokine; loss of function; mortality; mouse model; novel; oxidation; paracrine; protein expression; research study; response; restoration

DESCRIPTION (provided by applicant): Mammalian sterile 20 like kinase 1 (Mst1) is one of the most prominently activated serine/threonine kinases when cardiomyocytes (CMs) undergo apoptosis. Mst1 plays an important role in mediating ischemia/reperfusion (I/R) injury and cardiac dysfunction after myocardial infarction (MI). Mst1 also inhibits compensatory hypertrophy, thereby initiating a vicious cycle consisting of wall thinning, increases in wall stress, and chamber dilation. Despite the importance of Mst1 in regulating growth and death of CMs, how Mst1 is activated by pathological insults and how Mst1 mediates myocardial cell death are poorly understood. Genetic studies in Drosophila have suggested that hippo, a homolog of mammalian Mst1, belongs to a signaling cascade termed the hippo pathway, which plays an important role in regulating organ size through stimulation of apoptosis and suppression of cell proliferation. The cellular function of the hippo pathway appears to be conserved from Drosophila to mammals, indicating its fundamental importance. Our long-term hypothesis is that the mammalian hippo pathway regulates growth and death of CMs. In this study, we hypothesize: 1. K-Ras is activated by I/R through oxidation and serves as a critical upstream regulator of Mst1 at mitochondria. K-Ras, Rassf1A and Mst1 form a complex and phosphorylate mitochondrial proteins, including Bcl-xL, thereby stimulating apoptosis. 2. The function of the Rassf1A-Mst1 pathway during I/R is cell type- dependent, and activation of the Rassf1A-Mst1 pathway in cardiac fibroblasts could be salutary for the heart during I/R through suppression of cytokines. 3. Decreases in the nuclear localization of YAP promote myocardial injury, whereas restoration of YAP expression promotes myocardial survival and regeneration during chronic MI. We will address these issues using genetically altered (gain and loss of function) mouse models, as well as proteomic approaches. Addressing these issues will allow us to elucidate the role of signaling mechanisms both upstream and downstream of Mst1 in mediating survival, death and growth of CMs in response to I/R. The knowledge obtained from these experiments should be useful for developing specific strategies to limit myocardial injury in patients with ischemic heart disease.

描述（由申请人提供）：哺乳动物不育20样激酶1（Mst1）是心肌细胞（CM）发生凋亡时最显着激活的丝氨酸/苏氨酸激酶之一。 Mst1 在介导心肌梗死（MI）后的缺血/再灌注（I/R）损伤和心功能障碍中发挥重要作用。 Mst1 还抑制代偿性肥大，从而启动由壁变薄、壁应力增加和心室扩张组成的恶性循环。尽管 Mst1 在调节 CM 生长和死亡方面非常重要，但人们对 Mst1 如何被病理损伤激活以及 Mst1 如何介导心肌细胞死亡知之甚少。果蝇的遗传学研究表明，hippo 是哺乳动物 Mst1 的同源物，属于称为 hippo 通路的信号级联，该通路通过刺激细胞凋亡和抑制细胞增殖来调节器官大小。河马途径的细胞功能似乎从果蝇到哺乳动物都是保守的，这表明它的重要性。我们的长期假设是哺乳动物河马通路调节 CM 的生长和死亡。在本研究中，我们假设： 1. K-Ras 通过氧化被 I/R 激活，并作为线粒体 Mst1 的关键上游调节因子。 K-Ras、Rassf1A 和 Mst1 形成复合物并磷酸化线粒体蛋白（包括 Bcl-xL），从而刺激细胞凋亡。 2. I/R 期间 Rassf1A-Mst1 通路的功能依赖于细胞类型，心脏成纤维细胞中 Rassf1A-Mst1 通路的激活可能通过抑制细胞因子而在 I/R 期间对心脏有益。 3.慢性心肌梗死期间，YAP核定位的减少会促进心肌损伤，而YAP表达的恢复会促进心肌的存活和再生。我们将使用基因改造（功能获得和丧失）小鼠模型以及蛋白质组学方法来解决这些问题。解决这些问题将使我们能够阐明 Mst1 上游和下游信号机制在调节 CM 响应 I/R 的存活、死亡和生长中的作用。从这些实验中获得的知识应该有助于制定限制缺血性心脏病患者心肌损伤的具体策略。