# Mechanisms for Impaired Diabetic Oral Wound Healing

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $455,832

## Abstract

Project Summary
The ability to heal oral wounds is an important aspect of an individual's health and is negatively affected by
diabetes. Surprisingly little is known about the impact of diabetes on the molecular events of oral wound
healing. Our recently published studies demonstrate that activation of the transcription factor forkhead box O1
(Foxo1) in keratinocytes plays important but surprisingly, opposite roles in re-epithelialization of wounds in
diabetic and normoglycemic animals. Preliminary Data shows that keratinocytes promote connective tissue
healing under normal conditions through a FOXO1 dependent mechanism but inhibit connective tissue
formation in diabetic wounds. The goal of this proposal is to unravel the molecular mechanisms through which
FOXO1 differentially activates keratinocytes to promote or inhibit connective tissue healing depending upon
normoglycemic or diabetic conditions. The results will establish how FOXO1 may be an important therapeutic
target in promoting wound healing in diabetes. Aim 1 will establish mechanisms through which two key FOXO1
downstream targets (TGFβ1 and MMP9) are inversely modulated by diabetic conditions in vitro (high glucose
and advanced glycation end products) in gingival keratinocytes and compare the results with epidermal
keratinocytes. Aim 2 will establish mechanisms through which keratinocytes enhance connective tissue healing
in a FOXO1 dependent manner in normoglycemic wounds but inhibit it in diabetic wounds. These studies will
focus on the impact of FOXO1 in organizing the expression of factors by keratinocytes that stimulate fibroblasts
and endothelial cells in normal conditions but fail to do this in diabetic conditions. The goal of Aim 3 is to carry
out translational studies and establish functional to rescue diabetic healing. They will determine whether
modulation of FOXO1 downstream targets reverses diabetes impaired gingival and dermal healing and whether
FOXO1 is a good therapeutic target to improve diabetic healing. The proposed studies are strongly supported
by Preliminary Data, will definitively test whether FOXO1 plays a central role in impaired diabetic oral wound
healing and will provide the basis for future studies by establishing whether its inhibition has therapeutic
value.

## Key facts

- **NIH application ID:** 9987307
- **Project number:** 5R01DE019108-10
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DANA T GRAVES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $455,832
- **Award type:** 5
- **Project period:** 2009-09-25 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987307

## Citation

> US National Institutes of Health, RePORTER application 9987307, Mechanisms for Impaired Diabetic Oral Wound Healing (5R01DE019108-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987307. Licensed CC0.

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