Roman G. Ginnan, PhD

Vascular pathologies such as restenosis, vein graft intimal hyperplasia, and atherosclerosis are characterized by dramatic phenotypic changes to vascular smooth muscle (VSM) cells, increased VSM cell proliferation, migration, and apoptosis accompanied by a significant inflammatory response. Secreted growth factors such as Platelet derived growth factor (PDGF) and pro-inflammatory cytokines such Interleukin-1b (IL-1b) are important determinants of the cellular functions associated with the progression of these vascular diseases. PDGF and IL-1b exert their influence by initiating protein kinase-dependent phosphorylation events and protein-protein interactions through direct activation of protein kinases and by increasing the intracellular levels of reactive oxygen species (ROS). A key signaling molecule mediating many of these cellular functions is ERK1/2, a member of the MAPK family of proteins. Our recent work has uncovered a significant role for PKCd in mediating both PDGF and IL-1b-dependent activation of ERK1/2 in VSM cells. PKCdelta is a member of large family of multifunctional serine/threonine protein kinases that has been implicated in multiple VSM cell functions including contraction, proliferation, and migration. PKCdelta is unique among its family members in that it also can be phosphorylated on multiple tyrosine residues in both its regulatory and catalytic domain. PKCdeltaýs tyrosine phosphorylation makes it an attractive candidate for protein-protein interactions and being responsive to increases in intracellular ROS levels. The functional consequences of these tyrosine phosphorylation events are not clear in VSM cells. The overall goal of research is to elucidate the mechanisms by which PKCdelta mediates PDGF- and IL-1delta-dependent signaling pathways in VSM cells and to understand the functional relationship between PKCdeltaýs catalytic activity and its tyrosine phosphorylation in VSM cells. Furthermore, the understanding of PKCdeltaýs role in these crucial signaling pathways is applied to determining PKCdýs role in mediating VSM cellular functions such as cell proliferation, migration, and apoptosis, all of which contribute to vascular disease.