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）：当心肌细胞（CMS）经历凋亡时，哺乳动物无菌20像激酶1（MST1）是最突出的丝氨酸/苏氨酸激酶之一。 MST1在介导缺血/再灌注（I/R）损伤和心肌梗塞后心脏功能障碍（MI）中起着重要作用。 MST1还抑制补偿性肥大，从而启动了由壁变薄，壁应力增加和腔室扩张组成的恶性循环。尽管MST1在调节CMS的生长和死亡方面的重要性，但MST1如何被病理侮辱激活以及MST1如何介导心肌细胞死亡的理解很少。果蝇中的遗传研究表明，Hippo是哺乳动物MST1的同源物，属于称为河马途径的信号传导级联反应，该级联途径在调节器官大小中通过刺激细胞凋亡和抑制细胞增殖起着重要作用。河马途径的细胞功能似乎是从果蝇到哺乳动物的保守，表明其基本重要性。我们的长期假设是，哺乳动物河马途径调节CMS的生长和死亡。在这项研究中，我们假设：1。K-RAS通过氧化而被I/R激活，并作为线粒体MST1的关键上游调节剂。 K-RAS，RASSF1A和MST1形成一种复杂的磷酸化线粒体蛋白，包括BCL-XL，从而刺激细胞凋亡。 2。在I/R期间，RASSF1A-MST1途径的功能取决于细胞类型，并且通过抑制细胞因子，心脏成纤维细胞中RASSF1A-MST1途径的激活可能对I/R的心脏表示敬意。 3。YAP核定位的降低会促进心肌损伤，而YAP表达的恢复会促进慢性MI期间的心肌存活和再生。我们将使用遗传改变（功能的增益和丧失）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上游和下游信号传导机制在介导对I/R的介导CMS的生存，死亡和生长中的作用。从这些实验中获得的知识对于制定特定策略以限制缺血性心脏病患者的心肌损伤应该很有用。