# Microglia Mediated Inflammation in the Diabetic Retina

> **NIH NIH R01** · UNIVERSITY OF TEXAS SAN ANTONIO · 2022 · $360,811

## Abstract

Project Summary
In the diabetic retina disruption of fractalkine (FKN) signaling induces fibrin(ogen) deposition, increased
production of IL-1 by microglia, vascular and neuronal damage. But, how FKN and its receptor, CX3CR1,
regulate microglia activation and retinal pathology is unknown. In humans, two single nucleotide
polymorphisms in the CX3CR1 locus (hCX3CR1-I249/M280) that show defective binding to FKN, play a key role
in inflammation during diabetes. Induction of diabetes in a mouse model expressing the human CX3CR1-
I249/M280 revealed accelerated neuronal loss in the retina, and systemic inflammation caused microglial
clustering and upregulation of pro-inflammatory cytokines. Thus, the FKN/CX3CR1 signaling pathway plays an
under-appreciated role in diabetic retinopathy (DR), perhaps via inflammatory processes. However, there is a
gap in knowledge regarding the exact relationship among FKN/CX3CR1 signaling, microglial activation and
cell damage (neuronal and vascular) in a diabetic host in which hyperglycemia and repeated episodes of
systemic inflammation occur. The central hypothesis is that FKN is neuroprotective in DR by blocking microglia
activation and the subsequent vascular permeability and inflammatory changes that are characteristics of DR.
The following specific aims will test the mechanism by which sustained microglial activation by fibrin(ogen)
potentiates neuronal and vascular endothelial cell damage. Utilizing experimental mouse models of diabetes
combined with systemic endotoxemia the following specific aims are proposed.
Specific Aim 1. Determine the role of microglia in the initiation and progression of diabetic
retinopathy. This aim will test the hypothesis that FKN binds to CX3CR1 polarizing microglia towards an anti-
inflammatory pathway early in disease. Therefore, a) microglia depletion in diabetic mice at acute and chronic
stages of disease, and b) peripheral fibrin(ogen) depletion will be used, to demonstrate that 1) dysregulated
microglia in response to fibrin(ogen) induce pro-inflammatory actions and oxidative damage that contribute to
neuronal damage and 2) that regulation of microglia activation can be harnessed to prevent vision loss.
Specific Aim 2. Determine the neuroprotective effects of soluble FKN to mitigate microglia activation
and rescue neuronal and vascular damage. FKN is expressed on neurons as a transmembrane protein,
acting as a membrane-bound adhesion molecule (mFKN) or as a soluble protein (sFKN) upon cleavage from
cell surfaces. Adeno-associated viral vectors will be used to express sFKN or mFKN in neurons to test the
hypothesis that pathways that enhance FKN signaling via its soluble domain are neuroprotective and will
prevent vision loss. Approaches will be implemented to also determine the synergistic effect of sFKN and anti-
fibrin approaches to prevent vision loss in mice lacking CX3CR1 or expressing the human CX3CR1I249/M280
variant.

## Key facts

- **NIH application ID:** 10460458
- **Project number:** 5R01EY029913-04
- **Recipient organization:** UNIVERSITY OF TEXAS SAN ANTONIO
- **Principal Investigator:** Astrid E Cardona
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,811
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460458

## Citation

> US National Institutes of Health, RePORTER application 10460458, Microglia Mediated Inflammation in the Diabetic Retina (5R01EY029913-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10460458. Licensed CC0.

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