ROLE OF P38 MAPK AND PP2C IN ISCHEMIC INJURY AND PROTECTION

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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.