# Control of aging and age-related diseases by extracellular matrix microenvironment

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $319,800

## Abstract

ABSTRACT
Aging is the single largest risk factor for many common diseases that burden public health. The major goal of this
application is to understand the pathogenesis of age-related diseases resulting from deleterious alterations of the dermal
extracellular matrix (ECM) microenvironment. This application employs novel mouse models of accelerated skin
connective tissue aging and therefore addresses a need identified by the NIH for development and characterization of
animal models for aging research (FOA PA-13-155).
The dermis comprises the bulk of skin and confers strength and resiliency. The dermis is primarily composed of
collagenous ECM. This ECM is produced, organized and maintained by fibroblasts. Our recent studies reveal that dermal
fibroblasts, in aged human skin in vivo, express elevated levels of a protein called CCN1. We find that elevated CCN1
causes fibroblasts to express altered levels of numerous secreted proteins that deleteriously impact skin function.
CCN1-induced alterations include: 1) reduced collagen production, which causes dermal thinning; 2) elevated levels of
collagen-degrading enzymes, which cause ECM fragmentation; and 3) increased levels of proinflammatory cytokines,
which promote aging associated inflammation (inflammaging). Importantly, these CCN1-induced alterations are major
features of aged human skin. We refer collectively to these alterations as “Age-Associated Dermal Microenvironment
(AADM)”.
Based on these data, we have created a transgenic mouse model (CCN1col-tg) with increased expression of CCN1 by
fibroblasts. These mice display accelerated aging and AADM. In addition, these mice exhibit significantly increased
susceptibility to formation of skin tumors. Based on our findings, we hypothesize that age-related elevation of CCN1 by
dermal fibroblasts causes AADM, which promotes skin aging and age-related skin diseases.
Specific Aim 1 will test the hypothesis that healthy young dermal microenvironment functions as tumor suppressor, while
AADM act as a tumor promoter. Specific Aim 2 will determine molecular mechanisms by which CCN1 promotes
AADM. Specific Aim 3 will utilize mechanism-based intervention to inhibit CCN1-induced AADM and skin cancer
formation.
This proposal is innovative and highly impactful because it: 1) utilizes novel mouse models to investigate new concepts of
aging, i.e. AADM and its role in aging and age-related diseases, and 2) brings into focus the importance of the interplay
between the extracellular microenvironment and decline of cell function during the aging process.

## Key facts

- **NIH application ID:** 10163759
- **Project number:** 5R01AG054835-05
- **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:** 2021
- **Award amount:** $319,800
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163759

## Citation

> US National Institutes of Health, RePORTER application 10163759, Control of aging and age-related diseases by extracellular matrix microenvironment (5R01AG054835-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10163759. Licensed CC0.

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