# Mechanisms Underlying Impaired Diabetic Wound Healing

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $393,750

## Abstract

ABSTRACT
Persistent unresolved inflammation impairs diabetic wound healing. The function and fate of wound
monocyte/macrophages (mϕ) hold the key to the outcome of wound inflammation. This proposal builds on
observations originating from live functional wound macrophages (wmϕ) and wound fluid derived from chronic
wounds of patients which were then developed further using experimental models. Given current ambiguity in
macrophage nomenclature, and proposed misfit of wmϕ with the M1/M2 nomenclature, for this proposal we
classify wmϕ based on the pro-inflammatory (mϕinf) or pro-resolution/healing (mϕheal) functional states. We
have reported that i) successful wmϕ efferocytosis (Eff) helps resolve inflammation; and ii) Efferocytosis
severely impaired (Efflo) in wmϕ of diabetic wounds causing unresolved inflammation, and iii) correction of Efflo
with recombinant MFG-E8 (rMFG-E8) in wmϕ of diabetic wounds resolves inflammation and promotes wound
healing. Our laboratory was the first to report a critical role of miRNA-21 in the regulation of wound
inflammation. We recently reported the framework of a new paradigm proposing that the plasticity of wmϕ at
the wound-site is a major determinant of the state of wound inflammation. The current proposal seeks to
characterize this paradigm with emphasis on two novel aspects: (i) that miR cargo captured in extracellular
vesicles (EVs) at the site of wound inflammation determine the fate of wmϕ and state of inflammation; and (ii)
that at the site of diabetic wound inflammation miR is epigenetically silenced (methylated) such that
inflammation persists. The following three aims are proposed: Aim 1: Test miR-21 and efferocytosis as critical
determinants of monocyte/macrophage fate at the wound-site. §1.1 A unique subset of wmϕ convert from mϕinf
 mϕF; miR-21 encapsulated in wound-site extracellular vesicles (EV) are delivered to wmϕ to cause such
conversion. §1.2 Another subset of wmϕ undergoes mϕinfmϕheal; this subset plays a critical role in resolution
of wound inflammation and healing. Aim 2: Determine how diabetes redirects the fate of wmϕ causing
derailment of healing. §2.1 Diabetic conditions cause miR-21 epigenetic silencing in wmϕ (miR-21lo). Such
deficit, in combination with impaired efferocytosis (Efflo), stalls wmϕ in mϕinf; §2.2 In diabetic wmϕ, correction of
miR-21 and efferocytosis advances diabetic mϕinfmϕheal/mϕF resuming healing. Novel macrophage-targeted
lipid nanoparticle (LNPmφ) will correct diabetic miR-21lo. Aim 3: Study live wmϕ and wound-edge tissue biopsies
isolated from diabetic wounds of patients testing whether: §3.1 transition of wmϕ to mϕF (or mϕheal) is
compromised in poorly controlled diabetics (HbA1c>9) where miR-21 is epigenetically silent; §3.2 correction of
miR-21 and efferocytosis advances diabetic wmϕ from mϕinfmϕheal/mϕF.

## Key facts

- **NIH application ID:** 10205045
- **Project number:** 5R01DK114718-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Sashwati Roy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205045

## Citation

> US National Institutes of Health, RePORTER application 10205045, Mechanisms Underlying Impaired Diabetic Wound Healing (5R01DK114718-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205045. Licensed CC0.

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