# Recycling of Metabolites from Ingested Outer Segments Supports Visual Function

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $493,877

## Abstract

Visual function depends on the intimate structural, functional and metabolic interactions between
the retinal pigment epithelium (RPE) and the neural retina. Photoreceptor (PR) cells have a high
rate of metabolism that is supported through a continuous supply of glucose and oxygen from the
choroidal vasculature. The RPE forms the outer blood retinal barrier and transports glucose to
the outer retina via GLUT1 transporters in both the apical and basolateral membranes. The RPE
spares glucose for the outer retina by oxidizing lactate generated through aerobic glycolysis in
the outer retina and fatty acids derived from ingested photoreceptor outer segments (OS). Thus,
we hypothesize that the RPE serves as the gatekeeper of retinal metabolic stability through
bioenergetics specializations that enhance retinal fuel availability and support photoreceptor
function. In this role, it is critical that RPE function be maintained over a lifetime, especially given
that these cells are post-mitotic. RPE oxidation of fatty acids and lactate maintains its
differentiation and PR function as changes in oxidative metabolism lead to RPE dedifferentiation.
We hypothesize that the beneficial effects of fatty acid oxidation (FAO) working in synergy with
ketogenesis will (1) provide energy for the RPE and prevent steatosis (2) reoxidize mitochondrial
NADH to facilitate lactate utilization, (3) decrease RPE reliance on glucose thereby sparing it for
the neural retina and (4) provide fuel for PR through ketolysis of βHB. Furthermore, we
hypothesize that lactate is not only a fuel for energy production in RPE, but by-products of lactate
oxidation regulate lysosomal pH and gene transcription. Our long-term goal is to identify the
pathways that control metabolic symbiosis in the outer retina to sustain normal vision over a
lifetime. The hypotheses will be tested in the following specific aims. Specific aim 1: To determine
whether oxidation of long chain fatty acids is necessary to maintain metabolic homeostasis and
differentiation of the RPE. Specific Aim 2: To determine how the coordinated activities of RPE
ketogenesis and PR ketolysis support visual function. Specific Aim 3: To determine whether
lactate produced through aerobic glycolysis in PR and Mϋller glia in the outer retina supports RPE
metabolism and differentiation as well as maintenance of lysosomal pH. Collectively these studies
demonstrate the symbiotic relationship among the metabolically specialized cells in the outer
retina. Damage to the RPE, PR or Mϋller cells can cause non-autonomous changes that
negatively affect the entire system and lead to vision loss.

## Key facts

- **NIH application ID:** 9973865
- **Project number:** 2R01EY026525-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kathleen Boesze-Battaglia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,877
- **Award type:** 2
- **Project period:** 2016-03-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973865

## Citation

> US National Institutes of Health, RePORTER application 9973865, Recycling of Metabolites from Ingested Outer Segments Supports Visual Function (2R01EY026525-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9973865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*