PROJECT SUMMARY Retinal dystrophy-caused vision impairment severely impacts the quality of life for millions of people world- wide. Despite advances in recent decades, current medicine still lacks safe and effective treatments for many blinding diseases. Neuroprotective therapies aimed at delaying neuronal loss and preserving visual function could, therefore, be a useful strategy for treating slow-progressing blinding diseases such as age-related macular degeneration and glaucoma. The cytokine ciliary neurotrophic factor (CNTF) is known to act as a potent neuroprotective agent in a variety of retinal degeneration models. However, chronic exposure to high doses of CNTF results in the suppression of visual function in spite of preventing neuronal death. In order to leverage the beneficial while avoiding the detrimental effects of CNTF, it is critical to understand CNTF signal- induced cellular events in the retina. To provide greater insight into ongoing CNTF clinical trials aimed at treating blinding diseases, we performed molecular genetic analyses in mouse retinal degeneration models infected with a viral vector we engineered to express the same human recombinant CNTF being used in clinical trials. We demonstrated that CNTF initially targets Muller glia, which in turn activate a signaling loop between Muller glia and photoreceptors, leading to photoreceptor survival. We also showed that CNTF signaling rapidly and extensively alters the retinal transcriptome, which may underlie the CNTF-mediated suppression of visual function. In addition, we have demonstrated that removal of a cytokine signaling inhibitor in rod photoreceptors is sufficient to enhance their survival in the absence of exogenous CNTF, indicating that modulation of endogenous cytokine signaling can promote photoreceptor viability. Moreover, our recent study has revealed that CNTF treatment profoundly impacts retinal metabolism, resulting in enhanced aerobic glycolysis and anabolism, elevated energy production, and restored retinal redox status. The proposed research will combine molecular and biochemical approaches to further our understanding on the cellular process elicited by CNTF in the retina. We will examine cell type-specific transcriptomic changes and altered metabolic pathways to fully assess effects of CNTF treatments on various cell types. We will evaluate the role of a key glycolytic enzyme in photoreceptor maintenance and survival. We will also determine the distinct functions of cytokine signaling components involved in the CNTF-induced metabolic changes. Outcomes of the proposed research will advance our knowledge of neuroprotection mechanisms, especially the role of metabolism in sustaining neuronal survival, and thus facilitate the development of more efficacious treatments for retinal degeneration.