Photoreceptor death underlies many types of retinal degeneration, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Our long-term goal is to understand mechanisms of photoreceptor survival. During retinal injury, Muller glia cells play a protective role by secreting pro-survival growth factors to protect remaining photoreceptors in a toxic environment. The signaling pathways that lead to growth factor induction are largely unknown. Therefore, elucidating the molecular mechanisms that regulate growth factor induction will be important for understanding the potential therapeutic properties of these important molecules and for identifying novel, more effective, treatments. The Wnt pathway is an essential signaling cascade that mediates retinal development and retinal stem cell proliferation and is a critical regulator of cell survival in degenerative conditions of the brain, such as Alzheimers disease. Several lines of evidence suggest that Wnt signaling is protective in the retina and that it may induce growth factors from Muller glia or act directly on photoreceptors. Our hypothesis is that Wnt signaling plays a pro-survival role during retinal degeneration. In this study we will delineate the role of Wnt signaling in the Muller glia- growth factor injury response using primary Muller glia cultures (Aim 1). To identify the role of Wnt signaling during retinal degeneration we will use viral vectors to over-express Wnt activators and inhibitors in primary retinal cultures and in vivo (Aims 2 and 3). Together, these experiments will advance our understanding of pathways regulating photoreceptor survival and will identify a new cellular signaling mechanism linking photoreceptors and Muller glia. Furthermore, the results from this study will demonstrate whether modifying the Wnt pathway can be used as a therapeutic strategy for retinal degenerations.
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