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基本成分；它们中的许多，如神经酰胺，鞘氨醇1-磷酸也是生物活性脂质，调节从细胞凋亡到血管生成的细胞功能。神经鞘脂的重要性在临床上得到了很好的认识，因为它们在神经鞘脂中毒中起着调节作用。它们是一大类由鞘脂代谢酶缺陷引起的遗传性疾病，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）的突变可导致遗传性感觉神经病变，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。我们发现鞘脂生物合成途径的酶及其代谢物是果蝇光感受器结构和功能的重要调节因子，并且该途径的调节可以抑制一系列光导突变体的视网膜变性。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传递的视觉信号和光感受器中的视紫红质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光感受器稳态。该项目的具体目标是：(1)进一步了解神经酰胺介导的光感受器信号传导和退化的破坏。(2)了解鞘脂生物合成途径的通量如何通过丝氨酸棕榈酰转移酶突变体的产生和表征来调节光受体的稳态。(3)研究鞘氨醇激酶及其代谢物在视紫红质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。研究鞘脂在果蝇光感受器和光转导中的功能，将为我们全面了解鞘脂的功能、控制其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的过程提供基础。这将为鞘脂相关疾病的治疗策略的设计和开发提供坚实的基础。

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.