# Targeted therapy to reverse TLR4/DLL4 dysregulation in diabetic wounds

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $91,858

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and are
increasing at an alarming rate. Failure of wound healing in T2D patients represents the most common cause of
amputation in the US with a 5-year mortality rate of nearly 50%. Thus, a critical need exists for understanding the
wound healing defects in T2D in order to develop targeted therapies. Published data from our lab and my new
preliminary data has identified that TLR4 signaling in diabetic wound macrophages upregulates the Notch ligand,
DLL4, and promotes inflammation in acute wounds. Further, in diabetic wound macrophages, the TLR4/DLL4
pathway is upregulated secondary to an epigenetic mechanism whereby increased MLL1, a histone
methyltransferase, on the Tlr4 promoter promotes increased TLR4 signaling. This increased TLR4 signaling (via
MyD88) upregulates DLL4 in diabetic wound Mφs and drives inflammation and pathologic healing in diabetes.
Our proposed studies will establish that TLR4 is epigenetically upregulated via an MLL1-mediated mechanism in
diabetic wound macrophages and directly regulates DLL4 expression. These results have led to our hypothesis
that increased TLR4 signaling in diabetic wound macrophages increases DLL4 which promotes chronic
inflammation and non-healing in diabetic wounds. Our data suggest that diabetic wound repair may be improved
via locally-targeted treatment with TLR4 inhibitor(s) and/or MLL1 inhibitor(s). To test our hypotheses, we will
pursue the following Aims: Aim 1: To examine the TLR4-dependent regulation of DLL4 in diabetic wound
macrophages in acute and chronic diabetic murine wound models. Aim 2: To determine if local
therapeutic blockade of TLR4 or MLL1 improves diabetic wound repair in acute and chronic murine
wound models.

## Key facts

- **NIH application ID:** 10065265
- **Project number:** 1F32DK126471-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Christopher Onoruoiza Audu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $91,858
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065265

## Citation

> US National Institutes of Health, RePORTER application 10065265, Targeted therapy to reverse TLR4/DLL4 dysregulation in diabetic wounds (1F32DK126471-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065265. Licensed CC0.

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