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.
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.
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