# Identifying the cause for photoreceptor-mediated retinal-pigmented epithelium atrophy

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $418,750

## Abstract

PI: Claudio Punzo
Project Summary
Retinal-pigmented epithelium atrophy (RPE) that results in geographic atrophy (GA) in humans is one of the
leading causes for blindness in the industrialized world. This is because there is currently no treatment
available to prevent RPE atrophy and thus GA, which is an advanced form of Age-related Macular
Degeneration (AMD). The disease is characterized by focal RPE cell loss. Because the RPE maintains
photoreceptor homeostasis, photoreceptors die as well, which then leads to blindness. Recently, it has been
recognized that the high metabolic demands of photoreceptors may contribute to disease progression in AMD,
in particular, because photoreceptors and RPE metabolism are tightly linked. Two key findings imply
photoreceptors in disease pathogenesis. First, the distribution of soft drusen and subretinal drusenoid deposits
mirrors the distribution of cones and rods, respectively. This has led to the proposal that the metabolic needs
of photoreceptors are what drives deposit formation. Second, macular translocation procedures, which were
developed to save macular cones from dying RPE cells revealed that the new region where the cones where
translocated redeveloped GA. Here it is thought that the high metabolic demands of cones are what causes
RPE stress. However, whether photoreceptor metabolism differs between AMD patients and non-diseased
individuals remained unclear. We recently showed that PRs of AMD patients display signs of nutrient
derivation as they upregulate genes associated with an adaptive response to a glucose shortage. By
mimicking this adaptive response in mouse photoreceptors we were able to induce a subset of pathologies that
are reminiscent of those seen in humans with AMD, including focal RPE atrophy. The goal of this project is to
identify what exactly causes the pathologies seen. We propose in aim 1 to further analyze our model and to
determine how RPE cells die. Thereafter, in aim 2, we will dissect genetically the signaling pathway that we
have used to manipulate photoreceptor metabolism in order to hone in on the metabolic changes that cause
disease. Finally, in aim 3, we will use metabolomics, lipidomics and transcriptomics to identify the underlying
gene expression changes that cause disease and test putative candidate mechanisms in vivo.
Accomplishment of the proposed research will help understand how photoreceptors can cause RPE atrophy.

## Key facts

- **NIH application ID:** 10178343
- **Project number:** 1R01EY032461-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Claudio Punzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178343

## Citation

> US National Institutes of Health, RePORTER application 10178343, Identifying the cause for photoreceptor-mediated retinal-pigmented epithelium atrophy (1R01EY032461-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10178343. Licensed CC0.

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