Ceramide Metabolism and Photoreceptor Homeostasis

描述（由申请人提供）：鞘脂是所有真核生物细胞膜的组成部分；其中许多像神经酰胺、鞘氨醇、鞘氨醇-1-磷酸（S-1-P）也是生物活性脂质，调节从细胞凋亡到血管生成的细胞功能。我们的长期目标是全面了解控制正常鞘脂代谢的酶的功能及其与细胞生长、分化和信号传导的其他途径的整合。为了解决我们的目标，我们以果蝇为模型系统研究鞘脂生物合成酶。

DESCRIPTION (provided by applicant): Sphingolipids are integral components of all eukaryotic cell membranes; many of them like ceramide, sphingosine, sphingosine-1 -phosphate (S-1-P) are also bioactive lipids regulating cellular functions ranging from apoptosis to angiogenesis. Our long-term goal is to comprehensively understand functions of enzymes that control normal sphingolipid metabolism and their integration into other pathways involved in cell growth, differentiation and signaling. To address our goal, we study enzymes of sphingolipid biosynthesis using Drosophila as a model system. This proposal is based on the observation that sphingolipid metabolism plays an important role in survival of photoreceptors. Our findings show that decreasing ceramide levels by genetic modulation of the sphingolipid biosynthetic pathway suppresses retinal degeneration in a set of phototransduction mutants. Recent studies in human patients show that mutations in enzymes of ceramide metabolism cause Retinitis Pigmentosa and Hereditary Sensory Neuropathy. Based on these findings, the focus of this project is to understand how ceramide metabolism contributes to maintenance of photoreceptor homeostasis and other cellular functions. We will elucidate in vivo functions of three enzymes that decrease ceramide levels - ceramidase that converts ceramide to sphingosine, ceramide kinase that converts ceramide to ceramide-1-phosphate and sphingosine kinase that converts sphingosine to S-1-P. While ceramide and sphingosine are pro-death, S-1-P is pro-growth. The relative level of these antagonistic metabolites, regulated by the biosynthetic enzymes, determines whether a cell survives or dies. The specific aims of the project are (1) study components downstream of ceramidase in suppression of retinal degeneration and elucidate ceramidase function using a mutant (2) generate ceramide kinase mutant and transgenic flies to study its functions (3) generate and analyze mutant and transgenic flies to define the role of sphingosine kinase in regulating levels of sphingolipid metabolites.