# Alleviating Reactive Carbonyl Species-Induced Progenitor Cell Dysfunction in Diabetic Wound Healing

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $374,752

## Abstract

PROJECT SUMMARY
Refractory wounds in diabetic patients often result in amputation. Bone marrow derived endothelial progenitor
cells (EPCs) actively participate in wound repair through angiogenesis after homing to the wounding site.
However, progenitor cell functions are impaired in diabetes with mechanisms poorly understood. Reactive
carbonyl species (RCS) are the intermediates and by-products generated during energy metabolism. Our pilot
studies demonstrate one of the most potent RCS and the major precursor of the advanced glycation endproducts
(AGE), methylglyoxal (MGO), exerted immediate inhibitory effects on progenitor cell functions in vitro. The
glyoxalase I (GLO1), the key enzyme detoxifying MGO, was deficient in diabetic EPCs. These observations
unveil an important message: Theses RCS actually play a major role in compromising progenitor cell function in
diabetes, and this is due to the deficient glyoxalase defense system. The Major Goal of this project is to
understand the molecular mechanisms of disrupted angiogenesis induced by RCS and to identify therapeutic
targets for diabetic wound repair. Our recent report has demonstrated that an endoplasm reticulum response
sensor, Inositol-Requiring Enzyme 1α (IRE1α), is essential to progenitor cell-mediated angiogenesis during
wound repair. The endothelial-specific deletion of IRE1α leads to aberrant wound angiogenesis in vivo. However,
how IRE1α functionality in EPCs is damaged in diabetes is not clear yet. Our pilot data strongly suggest that
MGO directly diminishes IRE1α’s ribonuclease (RNase) function, and that IRE1α activation in EPCs is severely
inhibited by MGO but rescued by GLO1 over-expression. We further found out that chronic wounds in diabetic
animals started to heal upon receiving GLO1 gene transfer in vivo. Based on these findings, we propose Central
Hypothesis that accumulated MGO in diabetes compromises progenitor cell function via interfering with IRE1α
function, resulting in disrupted angiogenesis and delayed wound healing. To test the hypothesis, we propose
Three Specific Aims: 1) Elucidate mechanisms by which MGO causes EPC dysfunction and IRE1α deficiency
in diabetes in vitro; 2) Determine the molecular basis for MGO-induced IRE1α deficiency in vitro; 3) Determine
the therapeutic effects of lowering MGO in diabetic wound healing in vivo. Our proposed studies will use newly
developed Liquid chromatography–mass spectrometry (LC-MS) protocol to quantify free MGO accumulation in
human plasma and diabetic foot ulcer tissues, representing the first effort to acquire the dynamic changes of free
MGO generation in the microenvironment. We will employ both gain-of-function and loss-of-function technologies
for gene manipulations, IRE1α gene engineered animals, and a newly established chronic diabetic wound animal
model with cell therapies. Our project will allow us to uncover novel molecular mechanisms of impaired
angiogenesis and wound healing in diabetes in which RCS-induced prog...

## Key facts

- **NIH application ID:** 10445242
- **Project number:** 5R01DK119222-04
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** TERRENCE J. MONKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,752
- **Award type:** 5
- **Project period:** 2019-08-02 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445242

## Citation

> US National Institutes of Health, RePORTER application 10445242, Alleviating Reactive Carbonyl Species-Induced Progenitor Cell Dysfunction in Diabetic Wound Healing (5R01DK119222-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445242. Licensed CC0.

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