# The Role of sEV-associated miR-146a in Tissue Repair

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2022 · $46,752

## Abstract

ABSTRACT
Cutaneous wounds represent a significant healthcare issue and since 1997, no treatment for chronic wounds
has received FDA approval. Contributing to this treatment desert is the complexity of the wound healing process
and the relatively understudied field of how these activities are dysregulated and exploited in chronic wounds
and cellular transformation. Our previous work demonstrated that the cadherin, desmoglein 2 (Dsg2) is a
pleiotropic protein that modulates mitogenic signaling and pro-migratory programming in both tumorigenesis and
wound healing. We have shown that Dsg2 is down-regulated in chronic wounds and that constitutive
overexpression of Dsg2 in the epidermis confers increased wound healing, hyperproliferation, and tumor
development. Highlighting the contribution of altered keratinocyte dynamics to the pathology of many
dermatological conditions including chronic wounds, psoriasis, and squamous cell carcinoma. Dsg2 is able to
modulate keratinocyte activities such as proliferation and migration through its regulation of downstream
signaling molecules including the pro-proliferative and migratory proteins: EGFR and c-Src. In addition to the
modulation of proteins, our lab has also demonstrated that Dsg2 regulates the cellular and small extracellular
vesicle (sEV) transcriptome. miRNAseq revealed that Dsg2 induced the dramatic depletion of miR-146a, which
is a potent regulator of the inflammatory response and has been shown to potentially regulate 4469 genes,
including the level of miR-155. Therefore, it was interesting to note the consequent increase of miR-155 in
response to Dsg2 expression. Recently, we have focused on identifying the upstream regulators of Dsg2, and
much to our surprise, miR-155 targets Dsg2, which should lead to its degradation, however, RNAseq of these
same cells lead to the realization that the level of the lncRNA, Dsg2-AS1, was also increased. It is well
established that lncRNAs can “sponge” miRNAs and inhibit the degradation of their targets. This led us to
consider a novel regulatory mechanism whereby Dsg2-AS1 sponges miR-155, allowing for a dramatic increase
in Dsg2 expression. Preliminary data demonstrates that this mechanism is at play during normal wound healing,
as evidenced by the increase in Dsg2 expression after the concomitant increase of miR-155 and Dsg2-AS1
during wound repair. In this proposal, we hypothesize that the regulatory loop that controls Dsg2 expression is
altered in chronic wounds such as in the context of diabetes, which results in perturbed keratinocyte activation
and therefore ineffective wound closure. Thus, the goals of this proposal are to elucidate the Dsg2 regulatory
network and its impact on keratinocyte proliferation and migration, and to demonstrate the ability of sEV-
encapsulated RNA species that target this network as a way to stimulate keratinocyte activation in wound repair.
The findings obtained from these studies will demonstrate the feasibility of sEVs as a ro...

## Key facts

- **NIH application ID:** 10538174
- **Project number:** 1F31AR080564-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Brianna Leigh Hill
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-27 → 2024-09-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538174

## Citation

> US National Institutes of Health, RePORTER application 10538174, The Role of sEV-associated miR-146a in Tissue Repair (1F31AR080564-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10538174. Licensed CC0.

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