Interactive Signaling Modules in Vascular Inflammation

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The competitive renewal of the program project application "Interactive signaling modules in vascular inflammation" is focused on the process of inflammatory changes in the vessel wall that lead to atherosclerosis. The program brings together seven independent investigators interested in the vascular biology. The theme of the program is to define molecular mechanisms important for pathologic inflammatory events with a focus on myeloid cells. The central hypothesis is that interactions between distinct signal transduction modules influence fundamental cellular processes such as cell-cell interaction, cell migration, inflammation, death and engulfment of apoptotic cells, ultimately altering the pathogenesis and progression of atherosclerosis. Each project in the program focuses on a unique aspect of the theme to advance our understanding of inflammatory vascular phenotypes. Project 1 (Hla) proposes to investigate the role of sphingosine 1-phosphate on macrophage inflammasome function and atherogenesis. This project shares several common interests with Project 2 (Wu), which is focused on PLCB regulation of macrophage apoptosis and atherogenesis. Project 3 (Han) focuses on the process of cell-cell recognition process by which apoptotic cells are cleared from the vascular wall. Thus, this project has common interests as projects 2 and 4. Project 4 (Shapiro) focuses on the novel role of the cell-surface molecule CD13 in the adhesion of myeloid cells to vascular endothelial cells, and explores this mechanism in vascular pathology. All the projects utilize molecular, biochemical, cell biological and in vivo mouse models. Thus three cores, administrative, fluorescence imaging and vascular histology and atherosclerosis are proposed to support the projects with state-of-the-art technology. All the projects and cores interact and mutually reinforce each other to achieve the goals of the program in a synergistic manner. Coupled with strong institutional support to the Center for Vascular Biology, it is anticipated that significant new insights on vascular inflammation and atherosclerosis will be forthcoming from this renewal program project application. RELEVANCE (See instructions): Inflammation in the vessel wall is important in atherosclerosis, which leads to heart attacks. Blood monocytes enter the vessel wall, differentiate into macrophages and sustain inflammation. This project will focus on new mechanisms of monocyte entry, macrophage inflammatory mechanisms, macrophage survival and engulfment of dead or apoptotic cells. These collaborative studies should lead to better understanding of atherosclerosis and provide potential new therapeutic directions to control atherosclerosis.