Ceramide Metabolism and Photoreceptor Homeostasis

神经酰胺代谢和感光器稳态

• 批准号: 8245706
• 负责人: USHA R ACHARYA
• 金额: $ 37.01万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245706
• 关键词: Affect; Afferent Neurons; Animal Model; Apoptosis; Arrestins; Biochemical; Biological Models; Blindness; Calcium; Cell membrane; Cell physiology; Ceramidase; Ceramides; Defect; Degenerative Disorder; Differentiation and Growth; Disease; Drosophila genus; Endocytosis; Engineering; Enzymes; Equilibrium; Eukaryotic Cell; Excision; Eye; Eye diseases; Failure; Family; Fibroblasts; Foundations; Ganglioside Sialidase Deficiency Disease; Genes; Genetic; Goals; Hereditary Sensory Neuropathy; Homeostasis; Human; Impairment; Inherited; Lead; Learning; Light; Lipids; Maintenance; Mammalian Cell; Measurement; Mediating; Membrane; Metabolism; Modeling; Multiprotein Complexes; Mutate; Mutation; Organism; Pathway interactions; Patients; Peripheral; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Photoreceptors; Phototransduction; Process; Protein Family; Proteins; Proteolysis; Recycling; Regulation; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Role; Second Messenger Systems; Serine; Services; Signal Transduction; Sphingolipidoses; Sphingolipids; Sphingosine; Structure; Testing; Transcript; Transferase; Transgenic Organisms; Vision; Visual; Work; angiogenesis; base; ceramide kinase; design; dihydrosphingosine 1-phosphate; enzyme pathway; fly; insight; loss of function; mutant; novel therapeutics; phospholipase C beta; photoreceptor degeneration; protein function; public health relevance; receptor; second messenger; serine palmitoyltransferase; sphingosine 1-phosphate; sphingosine kinase; synaptic function; therapeutic development; trafficking; treatment strategy; visual photoreceptor; visual process; visual processing

DESCRIPTION (provided by applicant): Sphingolipids are essential components of all eukaryotic cell membranes; many of them like ceramide, sphingosine 1-phosphate are also bioactive lipids regulating cellular functions ranging from apoptosis to angiogenesis. The importance of sphingolipids is clinically well appreciated due to their deregulation in Sphingolipidoses. They are a large group of inherited diseases caused by defects in enzymes of sphingolipid metabolism and are associated with retinal impairment. Mutations in serine palmitoyl transferase 1, the rate-limiting enzyme of the sphingolipid biosynthetic pathway leads to Hereditary Sensory Neuropathy, a common degenerative disorder of peripheral sensory neurons. Several studies have recently identified mutations in a ceramide kinase like gene leading to autosomal recessive Retinitis Pigmentosa in patients. This proposal is based on our findings that enzymes of the sphingolipid biosynthetic pathway and their metabolites are important regulators of Drosophila photoreceptor structure, function, and modulation of this pathway can suppress retinal degeneration in a set of phototransduction mutants. Maintenance of ceramide level in photoreceptors by enzymes of this pathway is important for viability of photoreceptors, visual signaling through Phospholipase C, and turnover of Rhodopsin 1 in photoreceptors. Based on these findings, the focus of this project is to continue to understand how sphingolipid metabolism regulates photoreceptor homeostasis. The specific aims of the project are: (1) To obtain further insight into ceramide mediated disruption of signaling and degeneration in photoreceptors. (2) To understand how flux through the sphingolipid biosynthetic pathway regulates photoreceptor homeostasis by generating and characterizing mutants in serine palmitoyltransferase. (3) To study the role of sphingosine kinases and their metabolites in trafficking of Rhodopsin 1 and Transient Receptor Potential (TRP) and in maintenance of calcium homeostasis mediated by TRP family of proteins. Delineation of the functions of sphiolipids in Drosophila photoreceptors and phototransduction will provide the groundwork for our long-term objective to comprehensively understand functions of sphingolipids, the enzymes that control teir metabolism, and the processes through which these enzymatic networks integrate into other pathways involved in sustenance of a eukaryotic organism. This will provide a strong foundation for design and development of therapeutic strategies for treatment of diseases associated with sphingolipids. PUBLIC HEALTH RELEVANCE: It is often said that our eyes are windows to the world. We use them in all aspects of our lives - work, service, learning etc. Unfortunately, blindness compromises these abilities. Inherited eye diseases cause blindness in over 300 million people worldwide. Studies in model organisms are fundamental for new therapeutic strategies since they are more amenable to detailed analyses. The eye of the fruit fly is an excellent model to understand normal pathways in the visual process and to pinpoint mutated genes that can lead to retinal diseases due to similarities between fly and human vision and because mechanisms that disrupt sight in flies also lead to human blindness. We have succeeded in saving a class of diseased fruit fly photoreceptors from dying by decreasing their content of special lipids called ceramide by engineering the diseased flies to produce ceramidase, a protein that metabolizes ceramide. In this proposal, we want to understand the normal functions of proteins involved in ceramide metabolism in the visual process with the hope that we can develop better strategies for treatment of diseases (including visual) associated with altered sphingolipid metabolism.

说明(申请人提供)：鞘磷脂是所有真核细胞膜的基本成分；其中许多如神经酰胺、鞘氨醇1-磷酸也是生物活性脂类，调节细胞功能，从细胞凋亡到血管生成。鞘磷脂的重要性在临床上得到了很好的认识，因为它们在鞘磷脂病中的调节松弛。它们是一大类遗传性疾病，由鞘脂代谢酶缺陷引起，并与视网膜损伤有关。鞘磷脂生物合成途径的限速酶丝氨酸棕榈酰转移酶1的突变导致遗传性感觉神经病，这是一种常见的外周感觉神经元退行性疾病。最近有几项研究发现，神经酰胺激酶样基因突变会导致患者发生常染色体隐性遗传性视网膜色素变性。这一建议是基于我们的研究结果，即鞘磷脂生物合成途径的酶及其代谢产物是果蝇光感受器结构和功能的重要调节因素，调节这一途径可以抑制一系列光转导突变体中的视网膜退化。通过这一途径的酶来维持光感受器中神经酰胺的水平，对于光感受器的活性、通过磷脂酶C的视觉信号以及视紫红质1在光感受器中的周转是重要的。基于这些发现，本项目的重点是继续了解鞘磷脂代谢如何调节光感受器稳态。该项目的具体目标是：(1)进一步深入了解神经酰胺对光感受器信号转导和变性的影响。(2)通过产生和鉴定丝氨酸棕榈酰转移酶突变体，了解神经鞘脂脂生物合成途径中的通量如何调节感光细胞的动态平衡。(3)研究鞘氨醇及其代谢产物在视紫红质1和瞬时受体电位(Trp)转运以及Trp家族蛋白介导的钙稳态维持中的作用。揭示果蝇光感受器和光转导系统中鞘磷脂的功能，将为我们全面了解鞘磷脂的功能、控制TeIR代谢的酶以及这些酶网络整合到与真核生物赖以生存的其他途径的过程奠定基础。这将为设计和制定治疗与鞘脂有关的疾病的治疗战略提供坚实的基础。 与公共健康相关：人们常说，我们的眼睛是通向世界的窗户。我们在生活的方方面面都在使用它们--工作、服务、学习等等。不幸的是，失明损害了这些能力。遗传性眼病导致全球超过3亿人失明。对模型生物的研究是新治疗策略的基础，因为它们更容易受到详细分析的影响。果蝇的眼睛是一个很好的模型，可以理解视觉过程中的正常路径，并定位突变的基因，这些基因可能会导致视网膜疾病，因为果蝇和人类的视力相似，而且果蝇的视力障碍机制也会导致人类失明。我们成功地拯救了一类患病果蝇的光感受器，通过减少它们被称为神经酰胺的特殊脂类的含量，通过工程使患病果蝇产生神经酰胺酶，神经酰胺是一种代谢蛋白质。在这项建议中，我们希望了解神经酰胺代谢相关蛋白质在视觉过程中的正常功能，希望我们能开发出更好的治疗与鞘磷脂代谢改变相关的疾病(包括视觉)的策略。