# Role of dermal extracellular matrix microenvironment in skin aging

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $317,750

## Abstract

ABSTRACT
The major goal of this grant application is to test the hypothesis that elevated matrix metalloproteinase-1 (MMP1) in aged
skin fibroblasts initiates fragmentation of dermal extracellular matrix (ECM), which in turn promotes the aging process
and age-related skin pathologies. This grant is written in response to National Institute on Aging Funding Opportunity
Announcement PA-13-155 (Development and Characterization of Animal Models for Aging Research).
Aging affects all individuals, and is a key risk factor for many common diseases. The major alterations in aged skin are
localized in the dermal connective tissue, manifested by thin, fragile skin. We found that MMP1, which initiates
degradation of collagen fibrils, which comprise the bulk of skin to provide strength and resiliency, is significantly
increased in aged human skin. This fragmentation creates an aberrant dermal ECM microenvironment, which disrupts the
structural integrity of the skin and impairs cellular functions by interrupting cell-ECM interactions. We hypothesize that
alteration of the collagenous ECM microenvironment drive age-related skin pathologies, such as increased fragility,
impaired vasculature support, poor wound healing, and skin cancer.
Based on above human skin in vivo data, we recently generated an inducible transgenic mouse (col-MMP1), which
specifically expresses MMP1 in skin fibroblasts, the source of elevated MMP1 in aged human skin. col-MMP1 mice
exhibit significantly accelerated skin aging, exemplified by thinning, increased fragility, wrinkling, and fragmented
dermal collagen fibrils. These features closely mimic those observed in aged human skin. Importantly, col-MMP1 mice
show substantially increased susceptibility to skin cancer/papilloma development, supporting the concept that aberrant
dermal ECM microenvironment promotes age-related skin cancer.
Based on these findings, we hypothesize that elevated MMP1 in aged dermal fibroblast alters dermal ECM
microenvironment, which in turn drives the aging process and mediates the pathogenesis of age-related skin diseases. This
proposal will test above hypothesis, by 1): determining molecular mechanisms by which age-related alteration of ECM
microenvironment impairs dermal fibroblast functions; 2) investigating the ability of direct enhancement of mechanical
force to stimulate cell function and thereby improve age-related ECM dermal microenvironment; and 3) Determine the
role of age-related dermal ECM microenvironment on keratinocyte cancer development caused by UV irradiation and
chemical carcinogens. This proposal is innovative and may have profound impact on the field of aging and age-related
diseases by identifying age-related ECM microenvironment as a key target for therapeutic intervention.

## Key facts

- **NIH application ID:** 9899818
- **Project number:** 5R01AG051849-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** GARY J FISHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,750
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899818

## Citation

> US National Institutes of Health, RePORTER application 9899818, Role of dermal extracellular matrix microenvironment in skin aging (5R01AG051849-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9899818. Licensed CC0.

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