Project Summary Retinitis Pigmentosa (RP) is an inherited retinal disease afflicting 1 in 4,000 people worldwide. The disease progresses initially by rod photoreceptor degeneration caused by mutations in rod-specific genes, although different mutations in different genes converge upon the same rod degeneration phenotype in this disease. However, it is the subsequent cone photoreceptor degeneration that causes loss in daylight color vision and ultimately, diminishing quality of life for most patients. While gene therapy to replace a mutated gene with a functional copy has been successful, given the heterogeneity in mutations and genes, it is difficult to treat all RP cases by targeting the rods. Instead, a generic therapy to preserve the cones upon rod degeneration may lead to a more comprehensive therapeutic option. Despite progress, the molecular mechanism for this secondary cone degeneration remains unclear. The goal of this proposed research is to determine whether the breakdown of the Blood-Retina-Barrier (BRB) plays a causal role in non-cell-autonomous cone death in RP. During the independent phase of this grant (R00 phase), we will explore the effect of removing the intra-retinal vasculature on cone survival (Aim 1) and identify the foreign protein and cells that infiltrate the retina upon BRB breakdown (Aim 2). Completion of the proposed aims will lead to the identification of key regulators of cone survival in mouse models of RP. Moreover, we may identify, for the first time, a causal relationship between BRB breakdown and secondary cone death, opening new cellular targets to prevent cone loss in patients with RP. Long-term, the approaches outlined in this grant can become the cornerstone for answering questions regarding how, in general, neurons and other supporting cells degenerate in neurodegenerative disorders across the central nervous system. The rigorous scientific training received during the K99 phase in the Cepko Lab at Harvard Medical School built a strong foundation for an independent career investigating the molecular mechanisms of retinal degeneration.