# The role of collagen VII in extracellular matrix protein secretion

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $115,311

## Abstract

Abstract
Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease for which there
currently is no cure. RDEB is caused by mutations in the gene encoding type VII collagen (C7), leading to
epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in
RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wounding and scar
formation, and squamous cell carcinoma, the single biggest cause of death in this patient group. The molecular
pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB and as such RDEB is a
paradigm for understanding the molecular basis of fibrosis. We have shown that RDEB pathogenesis is driven
by a radical change in extracellular matrix (ECM) composition and increased TGFβ signaling that is a direct result
of C7 loss-of-function in dermal fibroblasts. However, the mechanism of how C7 loss results in extensive fibrosis
has until recently remained unclear. Our now published work has identified a direct role for C7 in protein secretion
which when defective or absent leads to accumulation of intracellular proteins, and subsequent increases in
cellular stress and the initiation of a pro-fibrotic cascade of TGFβ signaling. This paradigm shifting work has shed
significant light onto the conundrum in the field presented by RDEB – why does RDEB develop life threatening
skin cancers while other forms of Epidermolysis Bullosa (EB), characterized by continued tissue damage and
non-healing wounds, do not? In parallel, and using patient cells, we have identified anti-viral drugs, which inhibit
the production and release of viral particles (a process known to hijack cellular transport pathways), are
normalizing RDEB secretion defects and therefore represent a novel therapeutic approach to treat RDEB by
preventing fibrosis. Furthermore, our work comparing RDEB with non-RDEB patient cells has identified
increased TGFβ signaling as a potential mechanism of disrupted protein secretion in non-RDEB cells, which is
independent of the protein defect in RDEB, and anti-viral drugs may represent a novel anti-fibrotic that could
have application to a wider range of diseases, beyond RDEB. Therefore, our proposal seeks to investigate
protein secretion defects we have identified in RDEB fibroblasts and determine the mechanism of action of anti-
viral drugs in reducing fibrosis. At the same time, we will assess the anti-fibrotic action of anti-viral drugs in a
preclinical mouse model of RDEB and if successful future steps (not part of this funding application) will be to
initiate a clinical trial of successful candidate drugs. Together, our integrated in vitro and in vivo studies will define
and characterize a novel mechanism of progressive fibrosis, and assess preclinical efficacy of new molecular
entities that can be translated into the clinic for improved patient treatment.

## Key facts

- **NIH application ID:** 11290984
- **Project number:** 7R01AR082944-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Andrew South
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $115,311
- **Award type:** 7
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11290984

## Citation

> US National Institutes of Health, RePORTER application 11290984, The role of collagen VII in extracellular matrix protein secretion (7R01AR082944-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11290984. Licensed CC0.

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