Home Investigators Robert O. Messing, M.D. Messing Lab Members Wen-Hai Chou, Ph.D.
Wen-Hai Chou, Ph.D. PDF Print E-mail
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I am interested in studying the molecular and cellular basis of neurological diseases, especially in ischemic stroke. Stroke is a potentially devastating neurological disorder with high morbidity and mortality. Thrombolytic agents such as tissue plasminogen activator (t-PA) are currently the only drugs available to reverse acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Therefore, there is great interest in developing treatments to limit reperfusion injury. In collaboration with Drs. Donna Ferriero and Clifford Lowell at UCSF, we found that PKCδ null mice show a striking 70% reduction in stroke size compared with wild type mice after transient middle cerebral artery (MCA) occlusion and reperfusion. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue, as well as impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. To confirm whether impaired neutrophil function was important for the improved stroke phenotype in PKCδ null mice, we treated mice with total body irradiation followed by transplantation with bone marrow from the opposite genotype. We found that transplantation reversed the stroke phenotypes in wild type and PKCδ null mice, which is consistent with an important role for neutrophil PKCδ in reperfusion injury. Understanding the molecular and cellular actions of PKCδ in reperfusion injury requires the identification of the unique targets of PKCδ in signaling pathways activated by ischemia and reperfusion. A novel chemical-genetics approach has been developed by Dr. Kevan Shokat at UCSF to identify immediate substrates of kinases. Based on this approach, we have generated a PKCδ-analog sensitive mutant (PKCδ-as) enzyme, and recently we succeeded in generating a knock-in mouse expressing PKCδ-as. With these reagents, we have the unique opportunity to identify direct substrates of PKCδ in response to stroke-reperfusion injury. The information obtained will reveal PKCδ signaling pathways activated during cerebral ischemia and reperfusion in neutrophils, and should facilitate the development of PKCδ-related therapeutic strategies.