# Defining the role of mutational burden in sustaining normal homeostasis during aging

> **NIH NIH DP1** · YALE UNIVERSITY · 2022 · $83,547

## Abstract

Project Summary
 The skin is a dynamic organ comprised of three main layers, the topmost layer being the
epithelium followed by the basement membrane and the dermis. Stem cells within the skin are
located within the basal layer which is the innermost layer of the epithelium. Beneath this layer
resides the basement membrane which is comprised of various proteins as well as proteoglycans
and separates the epithelium from the dermis. The dermis is the innermost layer of the organ and
contains numerous different types of cells but is primarily comprised of fibroblasts. These
fibroblasts secrete various proteins that are essential for skin structure. We have discovered
through DTA ablation and immunofluorescence that these fibroblasts appear to inhibit stem cell
proliferation as ablation resulted in hyperproliferative activity of stem cells within the tissue. This
relationship highlights the importance of fibroblasts in maintaining skin homeostasis as excess
stem cell proliferation has the potential to be detrimental to the skin as it can increase the risk of
cancer-causing mutations. The aim of our project is addressing the different mechanisms by
which the skin goes about repairing itself, and the effect of the different cellular components have
in maintaining skin homeostasis. The aim of our parent grant addresses the major question of
“how
normal
are cell behaviors are properly orchestrated on the single-cell and tissue-scale level during
homeostasis as the organism ages.
 Supplemental funding is requested to support Deandra Simpson for 24 months of
postbaccalaureate work to pursue a scientific goal and to prepare for and apply to Medical
Scientist Training Programs. Deandra will train and take on responsibility for the different aspects
of the research described in the supplemental proposal. As described in the “Research
Experience Plan”, Deandra will assist on a project focused on understanding the relationship
between fibroblasts and epithelial stem cell proliferation in Aim 1: new approaches to investigate
different phenomena that contribute to skin homeostatic control during regeneration and Aim 2:
learning how to genetically manipulate our model organism to measure how these changes lead
to disruption in skin homeostasis. Our most recent work seemed to demonstrate that the ablation
of fibroblasts increases epithelial stem cell proliferation in vivo. However, we still lack a detailed
molecular level understanding of the causes of these changes. Different genetic approaches will
be used to delineate the mechanism that led to these changes and the overall impact of fibroblasts
in maintaining skin homeostasis.

## Key facts

- **NIH application ID:** 10554682
- **Project number:** 3DP1AG066590-04S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Valentina Greco
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $83,547
- **Award type:** 3
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554682

## Citation

> US National Institutes of Health, RePORTER application 10554682, Defining the role of mutational burden in sustaining normal homeostasis during aging (3DP1AG066590-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10554682. Licensed CC0.

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