Regulation of Kinase Cascades by Lipid-Derived Second Messengers

Our laboratory is interested in understanding the mechanisms by which mitogenesis is controlled during the inflammatory process. Specifically, we are interested in the role that lipid-derived second messengers play in limiting cellular proliferation despite an inflammatory milieu. Understanding the role of these lipid second messengers may be of therapeutic potential for chronic inflammatory responses, such as atherosclerosis and restenosis. Our studies are designed to target signal transduction cascades which are activated by second messengers to limit proliferation during inflammation. Inflammatory cytokines, including interleukin-1, tumor necrosis factor and interferon gamma, induce ceramide formation. Ceramide is a lipid-derived second messenger, which stimulates differentiation, inhibits proliferation and induces apoptosis. Our studies have characterized multiple regulatory mechanisms by which ceramide induces cell growth-arrest in activated vascular smooth muscle cells. These mechanisms include direct regulation of kinases and subsequent formation of signal complexes by ceramide. Our laboratory employs biochemical, biophysical and molecular biology strategies to document direct interactions between lipid-derived second messengers and kinase cascades. An important element of our research effort is to target these lipid-regulated signaling cascades in animal models of vascular disease. Our laboratory is actively exploiting in vivo strategies that deliver cell-permeable ceramide analogues directly to the site of atherosclerotic lesions. The use of anti-mitogenic lipids as components of lipid-delivery systems for gene therapy is also being investigated.