# Understanding Skin Tissue Repair in Live Mammals

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $676,488

## Abstract

Skin protects our body against the environment, and its ability to repair upon injury is directly connected
to both disease and survival. Failure to properly repair injured tissue can result in chronic wounds, which are
associated with severe complications and even death. Multiple cell types, like epithelial cells and fibroblasts,
must coordinate their behaviors to achieve injury repair. These processes have so far mainly been studied in
genetically homogeneous mouse models. However, healthy skin contains many clones harboring somatic
mutations, including oncogenic Ras mutations which are the leading cause of Squamous Cell Carcinoma.
 How genetically diverse epithelial cells affect injury repair is unknown. The goal of this proposal is to
unravel how cell behaviors are properly orchestrated on the single-cell and tissue-scale level during repair. The
critical barrier to addressing these fundamental questions lies in the inability to study these dynamic processes
in an intact mammal. To this end, my laboratory has established an in vivo strategy to directly visualize and
manipulate epithelial cells and fibroblasts in the skin of live mice. We have previously used this strategy to define
the roles of epithelial cells and fibroblasts in homeostasis, and the complex spatiotemporal organization of
epithelial cell behaviors during repair. We hypothesize that epithelial cells and fibroblasts use flexible behaviors
to enable proper wound healing of genetically mosaic skin.
 We will first define how a mosaic epithelium responds to injury (Aim 1). Our preliminary results show that
a mosaic Hras mutant skin epithelium heals at a normal rate and does not induce tumors, but that WT and Hras
mutant cells exhibit different behaviors during repair. We hypothesize that the behavioral flexibility of WT cells
confers the ability to contain their Hras mutant neighbors and ultimately achieve normal injury repair. To test this,
we will define the epithelial cell behaviors and evaluate the roles of signaling pathways during injury repair of an
Hras-mosaic skin epithelium. We will then examine the roles of fibroblasts in contact with epithelial cells during
injury repair (Aim 2). We hypothesize that direct communication between fibroblasts in the upper dermis and
epithelial cells in the epidermis coordinates cell behaviors and repair. To test this, we will define the behaviors
and functions of fibroblasts in the presence of WT epithelial cells and an Hras-mosaic epithelium. We will achieve
both these aims by combining intravital microscopy with genetic and pharmacological manipulations of distinct
repair behaviors or resident cell types in vivo.
 The proposed experiments will allow us to dissect the coordination and functional significance of
distinct cell activities, populations, and interactions during repair using an integrated approach of cutting-edge
imaging technology, genetic manipulation, cell biology, and single cell sequencing. Given that many aspects of
injur...

## Key facts

- **NIH application ID:** 10907775
- **Project number:** 5R01AR072668-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Valentina Greco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $676,488
- **Award type:** 5
- **Project period:** 2018-03-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907775

## Citation

> US National Institutes of Health, RePORTER application 10907775, Understanding Skin Tissue Repair in Live Mammals (5R01AR072668-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10907775. Licensed CC0.

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