This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sphingolipids are a family of membrane lipids with important structural roles in the regulation of fluidity and subdomain structure of the lipid bilayer, especially lipid rafts. Several severe neural diseases are the consequences of aberrant sphingolipid metabolism. Many of these storage diseases are associated with blindness. Besides the associated retinal pathology in patients with sphingolipid storage diseases, the role of sphingolipids in the retina is an unexplored area. In recent years, the role of ceramide as a mediator of apoptosis has been well established and in a few reports, its role in photoreceptor cell death has been indicated. We hypothesize that ceramide acts as a second messenger in apoptosis of retinal photoreceptor cells. We are investigating in vivo models (rat and mouse) by quantifying the level of ceramide and expression of ceramide biosynthesis genes during the process of degeneration. At the same time we have collected a group of mouse models that are mutated in ceramide biosynthetic genes such as ceramide synthase, acid ceramidase knock-out mice. We are studying the structure and function of retina in these mice to understand how the level of ceramide in retinal cells will affect its morphology and function. We'll use these mice for breeding with classical retinal degeneration models such as rhodopsin knock-out mice and Rd10 mice to investigate if the progression of retinal degeneration in these mice is altered by genetic manipulation. We are also investigating the role of Ceramide kinase like (CERKL) gene, mutations in which is involved in human retinitis pigmentosa 26 (RP26).
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