Michigan Postdoctoral Pioneer Program, 2021

Collaborative PIs


Bethany Moore, Ph.D.

Interim Chair and Professor, Microbiology & Immunology
Galen B Toews MD Collegiate Professor of Pulmonary Care & Critical Medicine
Professor, Internal Medicine

Co - Mentor

Katherine Ann Gallagher M.D.


Abstract Project 1:


Role of TLR4 and Notch Signaling in Diabetic Wound Healing

The failure of wound healing in type 2 diabetic (T2D) patients represents the most common cause of amputation in the U.S. The molecular mechanisms that control macrophage (Mφ)/CD4+T cell interactions following injury are not well understood. Our preliminary data identify that TLR4 signaling in wound Mφs upregulates the Notch ligand, DLL4, and through interactions with the Notch 1 and 2 receptors on CD4+T cells promotes TH17 differentiation. Further, in diabetic wound Mφs the TLR4/DLL4 pathway is upregulated secondary to an epigenetic mechanism whereby increased MLL1, a histone methyltransferase, on the Tlr4 promoter promotes increased TLR4 receptor expres­sion. Importantly, we found that Notch receptors 1 and 2 are significantly increased on CD4+T cells in diabetic wounds, further promoting increased TH17 differentiation and the excess IL17 production in diabetic wounds. This suggests that targeted inhibition of this pathway using FDA-approved drugs with nanotechnology may be a novel approach to restore proper Mφ/CD4+T cell interactions required for effective wound repair. These results have led to our hypothesis that increased Notch signaling in diabetic wounds polarizes CD4+T cells in the wound towards TH17 and promotes chronic inflammation and non-healing. These studies will address unexplored mech­anisms of how Notch influences both normal and pathologic healing.

Abstract Project 2:


Role of prostaglandin pathway in diabetic wound healing

Our data show prostaglandin E2 (PGE2) is elevated in wound macrophages (Mφs)

from a diet-induced obesity (DIO) murine model of diabetes. Upregulation (via histone methylation) of the cytosolic phospholipase A2 (cPLA2) gene, whose protein product liberates arachidonic acid (AA) to initiate PGE2 production in DIO wound Mφs underlies the PGE2 increase. Additionally, elevated transforming growth factor (TGF)β in diabetic wounds augments miR-29b, which inhibits DNA methyltransferases (DNMTs), causing changes in the methylation status of the cyclooxygenase (COX)-2 gene to promote arachidonic acid metabolism towards prostaglandin production rather than leukotriene synthesis. These changes correlate with a persistence of pro-inflammatory Mφs in diabetic wounds and impaired bacterial phagocytosis and killing in these diabetic Mφs. We also found diabetic wound Mφs impair fibroblast migration to wounds. These results have led to our hypothesis that the PGE2 pathway is epigenetically regulated and increased in diabetic wound Mφs and this results in inflammation, impaired host defense and defective wound repair. Thus, wound Mφ function may be restored via Mφ-targeted treatment with COX inhibitors or EP2 receptor-specific antagonists. This project would expand our murine studies to patients with diabetes and work to explore how the PGE2 pathway would impact closure of wounds complicated by infection.