# Targeted Abrogation of the FXII-uPAR-pAkt2 Axis in Neutrophils for Treatment of Chronic Wounds

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $390,766

## Abstract

PROJECT SUMMARY
The overall goal of this proposal is to characterize the interaction between Factor XII (FXII) and urokinase
plasminogen activator receptor (uPAR) to design strategies that disrupt their signaling in neutrophils for treatment
of chronic wounds. Chronic, non-healing wounds represent a major health care burden, costing 25 billion dollars
annually in US health care costs, and are associated with high mortality. Current treatments for impaired wound
healing focus mainly on optimization of controllable healing factors, e.g., mechanical protection, nutritional
support and clearance of infections. Targeted approaches have been developed to date, including topical
application of growth factors however, with limited clinical efficacy. Moreover, these approaches only influence
wound healing end-points (e.g. proliferation and remodelling) but do not prevent upstream events such as
excessive neutrophil activation, neutrophil extracellular trap (NET) formation, or unbalanced neutrophil
proteolytic activity, all of which are persistent hallmark events in non-healing wounds. In this framework, we
propose to downregulate neutrophil activation and NET formation through targeted disruption of the FXII-uPAR-
pAkt2 axis. We identified that FXII-uPAR upregulate neutrophil functions. Specifically, we have shown that
following neutrophil activation, autocrine FXII signals through uPAR leading to phosphorylation of Akt2 on Ser474
and to neutrophil adhesion, chemotaxis, and NET formation. Disruption of FXII signaling in neutrophils resulted
in faster wound healing. Based on these findings, our central hypothesis is that selective inhibition of the FXII-
uPAR-pAkt2 axis in neutrophils will be therapeutically effective in treating chronic wounds.
In this application, our goals are to: 1) map the uPAR binding sites on FXII using recombinant FXII deletion
mutants and site-directed mutagenesis. These studies will provide the structural details for the design of FXII
inhibitory peptides that interfere with the FXII-uPAR interaction; 2) use a unique nanovesicle platform that is able
to bind exclusively on activated neutrophils and deliver FXII inhibitory peptides at wound sites. We will first
characterize the biologic effects of these loaded nanovesicles in vitro, and subsequently we will determine their
therapeutic effect in murine models of wound healing in vivo. We will 3) correlate these preclinical studies and
determine the constitutive activity of FXII-uPAR-pAkt2 using blood and wound samples from diabetic patients.
The end goal is to show the relative abundance of the FXII-uPAR-pAkt2 axis and downstream effectors in non-
healing wound pathology which will lay the foundation for future translational studies to inhibit its action.
Our scientific innovation is the mechanistic elucidation of the FXII-uPAR-pAkt2 signaling axis in neutrophil-
mediated pathology. Our technological innovation is the development of peptide nanomedicine strategies to
block this axi...

## Key facts

- **NIH application ID:** 10320385
- **Project number:** 5R01HL137695-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Evi X. Stavrou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,766
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320385

## Citation

> US National Institutes of Health, RePORTER application 10320385, Targeted Abrogation of the FXII-uPAR-pAkt2 Axis in Neutrophils for Treatment of Chronic Wounds (5R01HL137695-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10320385. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*