Atherosclerosis remains the leading cause of death in the developed world. The signaling pathways involved in this chronic inflammatory disorder of the vasculature are poorly understood. PKC isozymes are potentially critical intracellular mediators of atherosclerotic regulatory signals in vivo. Recent data are consistent with a specific role for PKC in angiogenic signaling in vitro and in the development of vascular complications of diabetes in vivo. One of the challenges in the PKC field is to dissect the distinct roles of individual isozymes of PKC in atherosclerosis. It is the long-term goal of the applicant to determine the isozyme specific functions of PKC in atherosclerosis in vivo with a view to developing novel pharmacological therapies aimed at retarding this process in humans. Presently, it is unknown which PKC isozymes are activated in atherosclerotic tissue in vivo. Thus, despite the recent development of specific PKC inhibitors for use in humans, the isozymes that represent the best potential targets in atherosclerosis have not been identified. The investigator's specific aims, therefore, are: 1) to identify isozyme specific PKC activation in atherosclerotic mouse models and to modulate their activity in these models; 2) to confirm isozyme specific activation in human atherosclerosis and to investigate the effects on endothelial function of inhibition of specific isozymes inpatients with hypercholesterolemia; and 3) to examine the relevance of specific isozymes to angiogenesis in vitro and in vivo. By working closely with a multidisciplinary group with a strong background in both basic and translational research the applicant strives to obtain the practical experience necessary to develop an independent career in clinical investigation. Focussed coursework in patient-oriented research will compliment practical experience obtained during the development of this application.
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