Grants and Contracts Details
Since ischemic heart disease is one of the leading causes of mortality in developed nations, discovery of underlying causes and potential new treatments of ischemia/reperfusion injury is crucial. Numerous studies have addressed the roles of activation of mitogen-activated protein kinases (MAPKs) in the modulation of ischemia/reperfusion injury. However, the results of these studies have yielded conflicting findings. These discrepancies may be due to the possibility that the MAPK subtypes [p38, c-Jun N-terminal kinase (JNK), and extracellular regulated kinase (ERK)] exhibit differential subcellular localization that may produce diverse actions. In addition to the direct activation of MAPKs during ischemialreperfusion, another aspect that has not been well studied is the role of protein phosphatases in regulating the activity of these kinases. The applicant's preliminary data also show that the selective ERK pathway inhibitor, PD98059, dramatically reduces myocardial infarct size in an in vivo rat model, whereas the p38 MAPK inhibitor, S8203580, has no effect. Therefore, the hypotheses for this study are that the intracellular localization of p38 MAPK, JNK, and ERK determine the effect of these MAPKs in ischemia/reperfusion and that phosphatases regulate the activity of these kinases during ischemia/reperfusion. The following specific aims will be tested: Specific Aim 1: To determine the intracellular localization of MAPKs under basal conditions and after activation. Specific Aim 2: To determine whether altered MAPK activity in specific subcellular compartments modulates infarct size during in vivo regional myocardial ischemia. Specific Aim 3: To determine the subcellular compartmentation and role of specific protein phosphatases in modulating myocardial MAPK activity. Completion of this study will provide novel evidence that subcellular compartmentation of MAPKs during ischemia/reperfusion affects the role of these kinases in the modulation of this cardiac stress. Furthermore, this study will determine whether ischemia/reperfusion directly activates MAPKs or indirectly through modulation of phosphatses.
|Effective start/end date||7/1/04 → 6/30/07|
- American Heart Association Ohio Valley Affiliate: $121,000.00
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