Ceramide Metabolism and Photoreceptor Homeostasis

神经酰胺代谢和感光器稳态

基本信息

批准号：
7599588
负责人：
USHA R ACHARYA
金额：
$ 35.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7599588
关键词：
1-Phosphatidylinositol 4-Kinase Address Anabolism Animal Model Apoptosis Arrestins Biological Models Cell Death Cell membrane Cell physiology Cells Ceramidase Ceramides Cessation of life Drosophila genus Dynamin Endocytosis Enzymes Eukaryotic Cell Excision Genetic Genetic Screening Goals Growth Growth and Development function Hereditary Sensory Neuropathy Homeostasis Human Lead Lipids Maintenance Mass Spectrum Analysis Membrane Metabolism Mutation Organism Pathway interactions Patients Phosphatidylinositols Phosphotransferases Photoreceptors Phototransduction Physiological Play Relative (related person)Research Personnel Retinal Degeneration Retinitis Pigmentosa Role Signal Transduction Sphingolipids Sphingosine Transgenic Organisms Work angiogenesis base cell growth ceramide 1-phosphate ceramide kinase enzyme pathway fly in vivo mutant photoreceptor degeneration programs serine palmitoyltransferase sphingosine 1-phosphate sphingosine kinase

项目摘要

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；其中许多人如神经酰胺，鞘氨醇，1-磷酸盐（S-1-P）也是调节细胞功能的生物活性脂质，从凋亡到血管生成。我们的长期目标是全面了解控制正常的鞘脂代谢的酶的功能，及其在细胞生长，分化和信号传导中涉及的其他途径中的整合。为了解决我们的目标，我们使用果蝇作为模型系统研究鞘脂生物合成的酶。该建议基于这样的观察，即鞘脂代谢在感光体的存活中起着重要作用。我们的发现表明，鞘脂生物合成途径的遗传调节降低了神经酰胺水平，可抑制一组光转导突变体中的视网膜变性。对人类患者的最新研究表明，神经酰胺代谢酶的突变会导致色素性视网膜炎和遗传性感觉神经病。基于这些发现，该项目的重点是了解神经酰胺代谢如何有助于维持感光体稳态和其他细胞功能。我们将阐明三种酶的体内功能，这些酶降低了神经酰胺水平 - 将神经酰胺转化为鞘氨酸的神经酰胺激酶，该酶将神经酰胺转化为神经酰胺，将鞘氨酰胺和鞘氨醇激酶转化为将鞘氨酸转化为S-1-P。虽然神经酰胺和鞘氨酸是促成死亡的，但S-1-P是增长的。由生物合成酶调节的这些拮抗代谢产物的相对水平决定了细胞是否存活还是死亡。 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.