# cGAS-STING signaling in diabetic retinopathy

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $387,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Retinal leukostasis and vascular leakage play important pathogenic roles in diabetic retinopathy (DR).
Accumulating evidence suggests that DR is not an isolated retinal disease. Although circulating monocytes are
the major leukocyte subset responsible for leukostasis, the underlying regulation for monocyte activation in DR
has not been well investigated, which represents a knowledge gap. Two independent and prospective clinical
studies reported that fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), has
robust therapeutic effects on DR. Our preliminary studies showed that PPARα levels are down-regulated in
circulating monocytes of diabetic patients and diabetic animal models. PPARα ablation alone induces monocyte
activation, including increased adhesion, migration, and phagocytosis, while fenofibrate attenuates monocyte
activation in diabetic mice. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)
pathway plays a crucial role in inflammation. We showed that cGAS and STING are up-regulated in monocytes
in a diabetic model and in PPARα-/- mice, and inhibition of STING attenuates monocyte activation and alleviates
retinal leukostasis. Therefore, we hypothesize that PPARα suppresses cGAS-STING signaling to alleviate
monocyte activation and retinal leukostasis in DR, and that this effect is mediated in part by the mitoprotective
function of PPARα in diabetic monocytes. To address this hypothesis, we will first investigate if PPARα
suppresses monocyte activation in diabetes to alleviate retinal inflammation and vascular leakage in DR. Using
monocyte-specific PPARα conditional KO (PPARαMCKO) mice and monocyte-specific PPARα transgenic
(PPARαMCTg) mice, we will determine if ablation of PPARα will exacerbate, while PPARα over-expression will
alleviate diabetes-induced monocyte activation (adhesion, migration, phagocytosis), retinal leukostasis, vascular
leakage, and acellular capillary formation. Toward the mechanism for the monocyte-regulating function of
PPARα, we will investigate if the anti-inflammatory effect of PPARα is through inhibition of cGAS-STING
signaling in monocytes in diabetes. We will compare cGAS-STING activation in monocytes of diabetic
PPARαMCKO, PPARαMCTg, and WT mice. Furthermore, we will investigate if PPARα ablation promotes cGAS-
STING activation in monocytes by exacerbating mitochondrial damage and cytosolic mtDNA release in DR. We
also propose to study if the cGAS-STING pathway activation in monocytes plays a causative role in retinal
inflammation and vascular leakage in DR. We will determine if a STING inhibitor or ablation of cGAS or STING
will ameliorate monocyte activation, retinal leukostasis and vascular leakage in diabetic mice. The proposed
studies will identify a novel interaction between PPARα and the cGAS-STING pathway in the regulation of
immunometabolism and retinal inflammation in DR. These studies will also elucidate a new mechanis...

## Key facts

- **NIH application ID:** 10339181
- **Project number:** 1R01EY033330-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jian-Xing Jay Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,500
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339181

## Citation

> US National Institutes of Health, RePORTER application 10339181, cGAS-STING signaling in diabetic retinopathy (1R01EY033330-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339181. Licensed CC0.

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