Ceramide Metabolism and Photoreceptor Homeostasis

神经酰胺代谢和感光器稳态

• 批准号: 6907795
• 负责人: USHA R ACHARYA
• 金额: $ 35.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907795
• 关键词: Drosophilidae; alcohol phosphotransferase; amidohydrolases; apoptosis; ceramides; endocytosis; enzyme activity; enzyme induction /repression; enzyme mechanism; genetic regulation; genetic screening; genetically modified animals; homeostasis; lipid metabolism; mass spectrometry; mutant; phenotype; phosphatidylinositol 3 kinase; retina degeneration; visual photoreceptor

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.

描述（由申请人提供）：鞘脂是所有真核细胞膜的组成部分;其中许多如神经酰胺、鞘氨醇、鞘氨醇-1-磷酸（S-1-P）也是调节从细胞凋亡到血管生成的细胞功能的生物活性脂质。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，以及它们与细胞生长、分化和信号传导等其他途径的整合。为了解决我们的目标，我们研究的鞘脂生物合成的酶使用果蝇作为模型系统。 这一建议是基于鞘脂代谢在光感受器的存活中起重要作用的观察。我们的研究结果表明，神经酰胺水平的神经鞘脂生物合成途径的遗传调节抑制视网膜变性的光转导突变体。最近对人类患者的研究表明，神经酰胺代谢酶的突变导致视网膜色素变性和遗传性感觉神经病。基于这些发现，本项目的重点是了解神经酰胺代谢如何有助于维持感光细胞的稳态和其他细胞功能。我们将阐明降低神经酰胺水平的三种酶的体内功能-将神经酰胺转化为鞘氨醇的神经酰胺酶，将神经酰胺转化为神经酰胺-1-磷酸的神经酰胺激酶和将鞘氨醇转化为S-1-P的鞘氨醇激酶。受生物合成酶调节的这些拮抗代谢物的相对水平决定了细胞的生存或死亡。该项目的具体目标是（1）研究神经酰胺酶下游组分抑制视网膜变性，并使用突变体阐明神经酰胺酶功能（2）产生神经酰胺激酶突变体和转基因果蝇，研究其功能（3）产生和分析突变体和转基因果蝇，以确定鞘氨醇激酶在调节鞘脂代谢物水平中的作用。