SC COBRE: HUMAN ALKALINE CERAMIDASE REGULATION OF ANGIOGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Angiogenesis, the process of formation of new capillaries from preexisting blood vessels, is essential for the proper organ development and tissue repair. However, uncontrollable angiogenesis may lead to pathologies such as chronic inflammation, diabetic retinopathy, rheumatoid arthritis, and growth of solid tumors. Angiogenesis is coordinately regulated by cytokines, chemokines, growth factors, and inhibitors. In addition to these proteinaceous factors, several lipid factors have been shown to play an important role in mediating angiogenesis. Prominent among them are sphingosine-1-P (S1P) and its analogs which potentiates growth factor-induced angiogenesis by bonding to G protein coupled receptors of the Edg receptor family. S1P is a metabolite of sphingolipids. It is generated from sphingosine through the action of sphingosine kianse. Sphingosine in turn is generated from hydrolysis of ceramide through the action of ceramidases. More recently, several studies demonstrate that ceramide induces growth arrest and apoptosis of endothelial cells. These results suggest that regulation of metabolism of sphingolipids may control angiogenesis. Our results for the first time demonstrate that the human alkaline phytoceramidase is a key enzyme that regulates the levels of ceramides and the analog of S1P, dihdyrosphingosine-1-P. This establishes the human alkaline phytoceramidase as a potential target for chemotherapeutic interventions of tumor angiogenesis and growth.