# PKA and Epac1 inhibit TLR4 to protect the diabetic retina

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $351,262

## Abstract

Diabetic retinopathy is the leading cause of blindness in working age adults; however, much of this blindness
occurs in the later phases of the disease due to proliferative disease or macular edema. Recently, the role of
inflammation has become a focus of potential therapies targeted to treat earlier stages and/or prevent
progression of the disease. While it is clear that a large number of cytokines/chemokines are increased in the
diabetic retina, the role of innate immunity has only recently been investigated. Recent work has
demonstrated that toll-like receptors (TLRs) are altered in diabetes. Work has also shown that TLR4 is
increased in the streptozotocin-induced diabetic retina. Additionally, TLR4 may have actions in retinal
endothelial cells (REC), as both TLR2/4 pathways are active in these retinal cells. Our preliminary data has
expanded on those findings to demonstrate that β-adrenergic receptors can decrease TLR4 signaling in the
diabetic mouse retina, as well as in both REC and retinal Müller cells. Supporting our findings in retina,
studies in macrophages also demonstrate that β-adrenergic receptors can regulate TLR4. The response to
Compound 49b was blocked when Epac1 or PKA were knocked down by siRNA, suggesting these proteins act
as damage associated molecular pattern molecules (DAMPs) regulating TLR4 signaling in the diabetic retina.
Our primary hypothesis for this proposal is that PKA and Epac1 can regulate TLR4 and may represent a key
pathway that controls retina damage in diabetes. Our overall goal is to better understand the role of
downstream mediators of β-adrenergic receptors in the regulation of TLR4 signaling in the diabetic retina,
with the intent of identifying key pathways in innate immunity that can be targeted for novel therapeutics.
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## Key facts

- **NIH application ID:** 9879167
- **Project number:** 1R01EY030284-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Jena J Steinle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,262
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879167

## Citation

> US National Institutes of Health, RePORTER application 9879167, PKA and Epac1 inhibit TLR4 to protect the diabetic retina (1R01EY030284-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9879167. Licensed CC0.

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