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

> **NIH NIH K99** · HARVARD MEDICAL SCHOOL · 2022 · $77,863

## Abstract

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.

## Key facts

- **NIH application ID:** 10348141
- **Project number:** 5K99EY032110-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Ryoji Amamoto
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,863
- **Award type:** 5
- **Project period:** 2021-05-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348141

## Citation

> US National Institutes of Health, RePORTER application 10348141, Elucidating the molecular and cellular mechanisms underlying cone survival in the peripheral retina in mouse models of Retinitis Pigmentosa (5K99EY032110-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348141. Licensed CC0.

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