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ROLE OF P38 MAPK AND PP2C IN ISCHEMIC INJURY AND PROTECTION

P38 MAPK 和 PP2C 在缺血性损伤和保护中的作用

基本信息

批准号：
7803550
负责人：
Yibin Wang
金额：
$ 39.27万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7803550
关键词：
Address Adult Affect Affinity Age Animal Model Apoptosis Apoptotic Biology Cardiac Cardiac Myocytes Cause of Death Cell Death Cell Membrane Permeability Cells Cessation of life Collaborations Complex Data Doctor of Medicine Doctor of Philosophy Energy Metabolism Event Extracellular Matrix Family Figs - dietary Functional disorder Gene Expression Profile Genetic Genetic Recombination Genomics Heart Heart failure Heat shock proteins Hydrogen Peroxide Immunoprecipitation In Vitro Individual Injury Investigation Ischemia Laboratories Lead Link MAP Kinase Gene MAPK14 gene Mammalian Cell Mammals Mechanics Mediating Medical Metabolic Metabolism Mitochondria Mitochondrial Proteins Mitogen-Activated Protein Kinase 12 Mitogen-Activated Protein Kinases Mitogens Molecular Mus Muscle Cells Myocardial Infarction Myocardium Nature Organ Organelles Oxidative Stress Pathology Pathway interactions Patients Pattern Peroxisome Proliferator-Activated Receptors Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiology Play Predisposition Principal Investigator Process Protein Isoforms Protein Kinase Protein Phosphatase Gene Protein phosphatase Proteins Proteomics Protocols documentation Regulation Reperfusion Injury Reperfusion Therapy Reporting Research Role Scheme Signal Pathway Signal Transduction Signaling Molecule Stress TP53 gene Tissues Transcriptional Regulation Transgenic Animals Transgenic Model Transgenic Organisms Ventricular Remodeling Work Yeasts base biological adaptation to stress data mining fetal human MAPK12 protein human MAPK14 protein in vivo insight knockout animal loss of function member mitochondrial dysfunction mitogen-activated protein kinase p38 mutant novel novel therapeutic intervention overexpression preconditioning prevent programs protein expression protein phosphatase 2C stress protein stressor transcription factor

项目摘要

Principal Investigator/Program Director (Last, First. Middle): Ping, Peipei (Wang, Project 3) PROJECT 3: ROLE OF P38a MARK AND PP2CK IN ISCHEMIC INJURY AND PROTECTION UCLA Project Leader: Yibin Wang, Ph.D. Co-Project Leader: Enrico Stefani, M.D., Ph.D. PHS 398 (Rev. 05/01) Page 181 Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. Principal Investigator/Program Director (Last, First, Middle): Ping, Peipei (Wang, Project 3) Project 3 will address the central theme of ischemic injury and protection from a perspective of cardiac remodeling and heart failure. An important deleterious consequence of myocardial infarction is the induction of pathological remodeling, which recent reports shown is characterized by mitochondrial dysfunction, including altered energy metabolism and apoptotic cell death. The intracellular signaling events that mediate stress-induced pathological remodeling and myocyte apoptosis involve intricate regulation by protein kinases and phosphatases. In this regard, ischemic injury potently induces a highly conserved Ser/Thr protein kinase, p38 MARK, that regulates mitochondrial energy metabolism and apoptosis. In our previous studies, targeted induction of p38 activity in the heart was sufficient to induce pathological remodeling and heart failure, whereas genetic inactivation of the p38a isoform significantly protects the heart against ischemic injury. Despite significant progress in this field, very little is known regarding stress signaling at mitochondria. To this end, the discovery of a novel protein phosphatase-2C isoform (PP2Cic) by Project 3 represents important new insight into signaling at this organelle. Preliminary data indicate that PP2dc is highly expressed in the heart with targeted localization to the mitochondria. Moreover, the findings demonstrate that PP2CK is down-regulated in the failing heart and indicate that overexpression of PP2CK protects cardiac cells against oxidative stress-induced injury. These exciting findings led to the central hypothesis of Project 3: The stress-activated protein kinase p38a MAPK and the mitochondrial protein phosphatase PP2CK are two important signaling components in ischemia-reperfusion injury and they contribute to the genesis of cardiac phenotype by modulating mitochondria function and myocyte apoptosis during ischemic injury. In collaboration with Projects 1, 2, and 4, the Heart Biology Core and the Proteomic Core, Project 3 will undertake a comprehensive analysis of the role of individual p38 isoforms and PP2dc in ischemic injury. Four specific aims are proposed: In collaboration with Project 1 and the Heart Biology Core, Aim 1 will investigate the role of p38 MAPKs in regulating mitochondrial function and modulating susceptibility to MPT. In collaboration with Project 2 and the Heart Biology Core, Aim 2 will investigate the in vivo role of individual p38 MAP kinase isoforms in modulating susceptibility to MPT in ischemia/reperfusion injury. In collaboration with the Proteomic Core, Aim 3 will utilize a functional proteomic approach to identify p38a- associated proteins in the heart to elucidate the subproteome of molecules involved in p38a signaling during ischemic injury and protection. Finally, in collaboration with Projects 1 and 4, Aim 4 will fully characterize the newly- discovered mitochondria-specific phosphatase, PP2dc, and explore its role in modulation of stress signaling and cardioprotection. The proposed studies will provide novel insights into the role of stress proteins in regulation of mitochondrial dysfunction during ischemic injury and can lead to new therapeutic approaches to heart failure.

主要研究者/项目负责人（最后，第一。中）：平、培培（王、项目3）项目3： P38 a和PP 2CK在缺血性脑损伤中的作用及意义保护 UCLA 项目负责人：王一斌博士联合项目负责人：Enrico Stefani，医学博士，博士 PHS 398（Rev. 05/01）第181页在整个应用程序的底部连续编号页面。不要使用后缀，如3a，3b。主要研究者/项目负责人（最后，第一，中间）：平，佩佩（王，项目3）项目3将从心脏的角度讨论缺血性损伤和保护的中心主题，重塑和心力衰竭心肌梗死的一个重要的有害后果是诱导病理性重构，最近的报道显示其特征在于线粒体功能障碍，包括改变能量代谢和凋亡性细胞死亡。介导应激诱导的细胞内信号事件病理性重构和肌细胞凋亡涉及蛋白激酶和磷酸酶的复杂调节。在在这方面，缺血性损伤有效地诱导高度保守的Ser/Thr蛋白激酶，p38 MARK，其调节线粒体能量代谢和凋亡。在我们以前的研究中，靶向诱导p38活性，心脏足以诱导病理性重塑和心力衰竭，而p38 a基因失活，同种型显著保护心脏免受缺血性损伤。尽管在这一领域取得了重大进展，关于线粒体的应激信号的研究。为此，新型蛋白磷酸酶-2C的发现项目3的PP 2Cic亚型代表了对该细胞器信号传导的重要新见解。初步数据表明PP 2dc在心脏中高度表达，靶向定位于线粒体。而且研究结果表明，PP 2CK在衰竭的心脏中下调，并表明PP 2CK的过度表达保护心肌细胞免受氧化应激诱导的损伤。这些令人兴奋的发现导致了项目3的中心假设：应激激活蛋白激酶 p38 aMAPK和线粒体蛋白磷酸酶PP 2CK是两个重要的信号通路，缺血-再灌注损伤，它们通过调节线粒体功能与心肌细胞凋亡与项目1、2和 4、心脏生物学核心和蛋白质组学核心，项目3将全面分析单个p38亚型和PP 2dc在缺血性损伤中的作用。提出了四个具体目标： 1和心脏生物学核心，目标1将研究p38 MAPK在调节线粒体功能中的作用，调节对MPT的敏感性。与项目2和心脏生物学核心合作，目标2将调查单个p38 MAP激酶亚型在缺血/再灌注中调节MPT易感性的体内作用损伤在与蛋白质组学核心的合作中，Aim 3将利用功能蛋白质组学方法来鉴定p38 a- 相关蛋白，以阐明参与p38 a信号传导的分子的亚蛋白质组。缺血性损伤与保护最后，目标4将与项目1和项目4合作，充分描述新的- 发现了特异性磷酸酶PP 2dc，并探索其在应激信号调节中的作用，心脏保护这些研究将为应激蛋白在调节细胞凋亡中的作用提供新的见解。线粒体功能障碍在缺血性损伤，并可能导致新的治疗方法，心力衰竭。