? Stroke remains the leading cause of disability and the third leading cause of death in the U.S. Although more stroke patients are treated with thrombolytic agents, all neuroprotection trials for stroke have failed so far and therefore, new pharmacological interventions are greatly needed. Protein kinase C (PKC) has been implicated in preservation of various organs from ischemic insults, however many of these studies have focused on cardioprotection. Ischemic episodes to the brain result in activation of several protein kinase C isozymes, however conflicting roles (both positive and negative) for PKC in the response of the brain to ischemic injury have been reported. This is potentially due to the use of pharmacological agents which do not discriminate between the PKC isozymes. I propose that select PKC isozymes play unique roles in the various response stages of cerebral ischemic insult and reperfusion damage. To support this hypothesis I found that delivery of a peptide inhibitor of deltaPKC at the initiation of reperfusion reduces the size of cerebral lesion caused by transient focal ischemia in vivo. In the proposed study I plan to address the molecular mechanism of deltaPKC involvement in cerebral ischemic and reperfusion injury. I will determine the abundance, distribution, and activity of deltaPKC in the brain during a time course of ischemia and reperfusion in a rat model of stroke. I will then analyze whether treatment with deltaPKC specific inhibitor and activator peptides that we have developed, alter the translocation of deltaPKC in vivo. In addition, I will study the affect of deltaPKC modulation on markers of apoptotic cell death. Finally, I plan to investigate the role of other PKC isozymes in ischemic and reperfusion damage by analyzing the effects of our PKC modulating- peptides on cerebral lesion following focal ischemia in vivo. ? ?
| Bright, Rachel; Steinberg, Gary K; Mochly-Rosen, Daria (2007) DeltaPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo. Brain Res 1144:146-55 |
| Bright, Rachel; Raval, Ami P; Dembner, Jeffrey M et al. (2004) Protein kinase C delta mediates cerebral reperfusion injury in vivo. J Neurosci 24:6880-8 |
