EY015128 Project Summary: Retinal remodeling This renewal is based on our discovery that retinal degenerations are two separate diseases. Acute primary photoreceptor degenerations turn into chronic neurodegenerations mimicking brain diseases called “pro- teinopathies”. The neurodegeneration is unremitting, slowly destroying the neural retina with > 90% loss of retinal neurons, severely impeding rescue. The proposal aims to profile proteinopathy molecules; identify net- works underlying metabolic collapse; map the nature and scope of rewiring and neuronal loss, and develop a pigmented Tg P347L rabbit model of human adRP. Aim 1. Profile neurodegenerative proteinopathy molecules in the neurodegenerative retina. Hypothesis. Retinal neurodegeneration is a proteinopathy. Outcomes: A comprehensive, proteinopathy finger- print spanning 6y of disease progression. Significance. Interventions for blinding diseases require survival of the retina. Neurodegeneration must be overcome. Aim 2. Characterize of the metabolic / signaling collapse of the ND retina. Hypothesis. ND corrupts neuronal signaling and energetics. Outcomes: Metabolome status for all neurons and glial cells spanning 6y of ND. Significance. If neurodegenerative retinas cannot sustain activity, therapeutic in- terventions are destined to fail. Metabolic network mapping may reveal druggable targets. Aim 3. Develop a pathoconnectome spanning mid and late ND. Hypothesis. Neural rewiring in the retina is driven by interactions between survivor and degenerating neurons. Outcomes. The survivorship and connectivity of the ND retina. Significance. Different rescue schemas have different targets and the status of each is critical. Aim 4. Develop a pigmented Tg P347L rabbit for retinal degeneration research. Hypothesis. A pigmented eye is optimal for studying of retinal degenerations. Outcomes. A long lifespan, eco- nomically viable, large-eye pigmented model suitable for the FDA Animal Model Qualification Program, imag- ing, and analysis of disease progression, rescue and ND interventions. Significance. Developing therapies for human retinal disorders will eventually have to proceed beyond mouse models. A pigmented rabbit is an ideal platform for intervention testing.