# Regulation of cutaneous wound healing by GCN2

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

Approximately 6.5 million Americans are diagnosed with a cutaneous chronic wound each year, costing the
healthcare system in the United States over 20 billion dollars annually. Often these chronic wounds are found
in geriatric individuals, up to 85% of patients with chronic wounds are over 65 years old, or in patients with
concurrent diseases such as diabetes, obesity, malnutrition, or substance abuse. Similarly, the failure to
properly heal wounds is a major problem for the Veteran population as presently there are over 9 million
Veterans over the age of 65, or about 38% of the total Veteran population. Often these patients are subjected
to a litany of various treatments, frequently without mechanistic justification, and they still lack adequate
resolution of their wounds. Therefore, a better understanding of specific causes of chronic wounds and a better
menu of treatment options is needed to address this unmet need. Once any type of chronic wound appears,
whether it is a diabetic ulcer, decubitus ulcer, or venous stasis ulcer, one of the primary limiting factors in
wound closure is the inability of epidermal cells to re-epithelialize the wound bed. Chronic wounds remain
arrested in the inflammatory phase with little to no migration of keratinocytes across the wound bed. Recent
data have demonstrated that an evolutionarily-conserved mechanism, called the Integrated Stress Response
(ISR), is crucial for normal re-epithelialization in human skin. The ISR consists of four distinct but related
protein kinases are activated by various types of environmental stress leading to the phosphorylation of the
same target protein, eukaryotic initiation factor 2 on its alpha subunit (eIF2α~P). The consequences of
eIF2α~P include a global inhibition of protein translation, which conserves vital cellular energy stores, and the
selective translation of genes associated with responding to the stress. Importantly, it was recently
demonstrated that the ISR is activated in differentiating keratinocytes in normal skin. Furthermore,
keratinocytes deficient for one of the eIF2α~P protein kinases (GCN2, which phosphorylates eIF2α~P during
epidermal differentiation) form abnormal, dyskeratotic skin lacking a normal barrier function. If GCN2
expression is knocked-out in human keratinocytes (an exon 12 deletion using CRISPR/CAS9), keratinocytes
are deficient in epithelial sheet migration without affecting individual cell motility. These data led to the
hypothesis that GCN2 is a critical component of the cutaneous wounding response, and that manipulation of
the ISR via pharmaceutical agents will improve wound healing. This last point is particularly intriguing, because
several drugs that regulate the ISR (either positively or negatively) are already in human clinical trials for
unrelated diseases which could accelerate bringing any drugs that showed promise rapidly into human trials.
The initial studies into the role of the ISR on wound healing in this proposal use model sy...

## Key facts

- **NIH application ID:** 10417023
- **Project number:** 5I01CX001956-03
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** DAN F SPANDAU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417023

## Citation

> US National Institutes of Health, RePORTER application 10417023, Regulation of cutaneous wound healing by GCN2 (5I01CX001956-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10417023. Licensed CC0.

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