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.
