Ceramide Metabolism and Photoreceptor Homeostasis

神经酰胺代谢和感光器稳态

• 批准号: 8107800
• 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/8107800
• 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; 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.

描述（由申请人提供）：鞘脂是所有真核细胞膜的基本组分;其中许多（如神经酰胺、1-磷酸鞘氨醇）也是调节细胞功能（从细胞凋亡到血管生成）的生物活性脂质。由于鞘脂在鞘脂病中的失调，鞘脂的重要性在临床上得到了充分的认识。它们是由鞘脂代谢酶缺陷引起的一大组遗传性疾病，并与视网膜损伤有关。丝氨酸棕榈酰转移酶1（鞘脂生物合成途径的限速酶）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导致患者常染色体隐性视网膜色素变性。这一建议是基于我们的研究结果，即鞘脂生物合成途径的酶及其代谢产物是果蝇光感受器结构、功能的重要调节剂，并且调节该途径可以抑制一组光转导突变体中的视网膜变性。通过该途径的酶维持光感受器中的神经酰胺水平对于光感受器的活力、通过磷脂酶C的视觉信号传导和光感受器中视紫红质1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脂代谢如何调节感光细胞的稳态。本课题的具体目标是：（1）进一步研究神经酰胺介导的光感受器信号转导和变性。(2)了解如何通过产生和表征丝氨酸棕榈酰转移酶的突变体，通过鞘脂生物合成途径调节光感受器的稳态。(3)研究鞘氨醇激酶及其代谢产物在视紫红质1转运和瞬时受体电位（TRP）中的作用，以及在TRP家族蛋白介导的钙稳态维持中的作用。描述鞘脂在果蝇光感受器和光转导中的功能将为我们的长期目标提供基础，以全面了解鞘脂的功能，控制teir代谢的酶，以及这些酶网络整合到真核生物维持的其他途径中的过程。这将为设计和开发用于治疗与鞘脂相关的疾病的治疗策略提供坚实的基础。 人们常说，我们的眼睛是世界的窗户。我们在生活的各个方面使用它们-工作，服务，学习等。不幸的是，失明会损害这些能力。遗传性眼病导致全世界超过3亿人失明。模式生物的研究是新的治疗策略的基础，因为它们更适合详细的分析。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途径，并确定突变基因，这些突变基因可能导致视网膜疾病，因为苍蝇和人类视觉之间的相似性，因为扰乱苍蝇视觉的机制也会导致人类失明。我们已经成功地挽救了一类患病的果蝇感光细胞免于死亡，通过减少它们的特殊脂质（称为神经酰胺）的含量，通过工程改造患病的果蝇产生神经酰胺酶，一种代谢神经酰胺的蛋白质。在这个提议中，我们希望了解参与神经酰胺代谢的蛋白质在视觉过程中的正常功能，希望我们可以开发更好的策略来治疗与鞘脂代谢改变相关的疾病（包括视觉）。