# Modulating retinal lipid biogenesis in diabetes for therapeutic effects

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $382,250

## Abstract

Project Summary
 Diabetic retinopathy is an increasingly common cause of visual impairment and blindness among
adults. Modern therapy has become increasingly effective, but remains insufficient to prevent vision loss in a
sizable proportion of patients. Early-acting and efficacious new remedies are needed, especially since the
prevalence of worldwide disease is increasing. A barrier to accomplishing this goal is a poor understanding of
the earliest causes of retinal injury in diabetes. In this application, we will address this barrier by studying early
changes in retinal metabolism during diabetes – changes that are likely to contribute to disease onset and that
can be targeted for therapeutic purposes.
 Hyperglycemia is the hallmark of all forms of diabetes and is directly related to its complications,
including diabetic retinopathy. Since glucose is the primary fuel of the retina, we investigated what pathological
effects might occur due to its excess supply in diabetes. Specifically, we discovered that diabetes is associated
with a fundamental shift in retinal metabolism away from tissue break down (catabolism) and towards tissue
building (anabolism). Among the largest changes is that of lipid biosynthesis, a pathway responsible for
generating a ubiquitous medium-chain fatty acid in mammalian cells, palmitate. In diabetes, retinal palmitate
synthesis is elevated by 70% compared to non-diabetic controls. Using targeted genetic manipulation of the
enzymes in the synthesis pathway, we determined that reduction of palmitate prevents vision loss in diabetes
whereas elevating its production accelerates the onset of visual abnormalities. We now ask how such signals
are related to disease development and what specific molecules are involved. Towards these goals, we
recently found that excess palmitate in the diabetic retina impacts several retinal enzymes that are regulated
by S-palmitoylation. The largest change was seen in retinal Ryanodine Receptor 2 (Ryr2) – an intracellular ion
channel that regulates calcium homeostasis – as it is hyper-palmitoylated in diabetes compared to non-diabetic
controls. In this application we will determine whether this molecular change is associated with pathology and
whether it can be reversed for therapeutic effects.
 We will address three major aims: (1) define the effect of diabetes on retinal Ryr2 palmitoylation and its
functional consequences; (2) delineate whether Ryr2-associated calcium flux in rods is dependent on retinal
lipid biogenesis; and (3) determine whether improving retinal lipogenic signaling in diabetes reduces diabetic
retinopathy severity. By accomplishing these aims, we could uncover essential root causes of diabetic
retinopathy and we may introduce novel targets for therapy directed at a very early stage of the disease
process.

## Key facts

- **NIH application ID:** 10503919
- **Project number:** 1R01EY034172-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rithwick Rajagopal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,250
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10503919

## Citation

> US National Institutes of Health, RePORTER application 10503919, Modulating retinal lipid biogenesis in diabetes for therapeutic effects (1R01EY034172-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10503919. Licensed CC0.

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