Elucidating the molecular and cellular mechanisms underlying cone survival in the peripheral retina in mouse models of Retinitis Pigmentosa

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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. In mouse models of RP, the cones in the central retina degenerate after rod death, but interestingly, the cones in the peripheral retina survive long-term. The goal of this proposed research is to understand the molecular and cellular mechanisms underlying peripheral cone survival in mouse models of RP. During the mentored phase of this grant (K99 phase), factors that may be sufficient (Aim 1) and/or necessary (Aim 2) for cone survival will be elucidated by cell type specific RNA sequencing, in vivo retinal electroporation, and temporally-regulated gene deletion. During the independent phase of this grant (R00 phase), the causal relationship between blood-retina-barrier breakdown and cone degeneration will be explored (Aim 3). Completion of the proposed aims will lead to 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 mentored phase of this grant is conducted under the guidance of Dr. Constance Cepko, whose lab has developed many techniques over the years to genetically manipulate the retina in vivo and discovered gene regulatory networks underlying retinal cell type specification. The scientific environment that surrounds the Cepko Lab at Harvard Medical School offers valuable opportunities for career development, helping to build a strong foundation for an independent career investigating the molecular mechanisms of retinal degeneration.