# Notch Signaling Dictates CD4+T cell Activation in Diabetic Wounds

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $73,062

## Abstract

PROJECT SUMMARY
 Secondary complications of type 2 diabetes (T2D), including impaired wound healing,
are increasing, and therapeutic options remain limited and only marginally effective. Failure
of wound healing in T2D patients represents the most common cause of amputation in the
US and has an a 5-year mortality rate of 50%. Thus, a critical need exists for understanding the
pathophysiology of T2D woundsto identify novel mechanisms that can be therapeutically targeted.
In normal wound healing, a coordinated immune response between macrophages (Mφs), and
CD4+T cells is critical for a controlled inflammatory response and tissue repair. Although the
molecular mechanisms that dictate these interactions following injury are not well understood, our
group and others have identified that Notch signaling plays a critical role in wound healing.
Depending on the specific ligand-receptor interactions, CD4+T cell activation results in
differentiation into a specific T cell phenotype. It has been observed that CD4+T regulatory (Treg)
cells are critical to ensure normal tissue repair, while TH17 phenotypes promote excess
inflammation and impair healing; however, the mechanisms that control CD4+T cell activation in
wound tissue are unknown. Our preliminary data show that increased Notch signaling between
Mφs/CD4+T cells in diabetes can lead to increased TH17, decreased Tregs, excess inflammation
and pathologic healing. While the precise regulation of Treg/TH17 differentiation during wound
repair is unclear, our preliminary data identify that the Notch ligand, DLL4, is upregulated in
diabetic wound Mφs, and that DLL4 interactions with the Notch 2 receptor on CD4+T cells
promotes an inflammatory TH17 phenotype as opposed to Treg differentiation. We hypothesize
that DLL4-mediated Notch receptor signaling in diabetic wounds polarizes CD4+T cells in
the wound towards TH17 and promotes chronic inflammation and non-healing and that
local blockade of DLL4 will decrease inflammation and improve healing in diabetic murine
wounds. To test our hypotheses, we will pursue the following Specific Aims:
 1) To identify the role of Notch 2 receptor activation on Treg/TH17 differentiation in acute
 and chronic diabetic murine wound models.
 2) To determine if genetic or local therapeutic blockage of DLL4 ligand limits TH17
 differentiation, decreases inflammation and improves diabetic wound repair.

## Key facts

- **NIH application ID:** 10313485
- **Project number:** 1F32DK130570-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Emily Caitlin Barrett
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $73,062
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313485

## Citation

> US National Institutes of Health, RePORTER application 10313485, Notch Signaling Dictates CD4+T cell Activation in Diabetic Wounds (1F32DK130570-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313485. Licensed CC0.

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