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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $92,945

## 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:** 10410587
- **Project number:** 3R01AG054835-05S1
- **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:** $92,945
- **Award type:** 3
- **Project period:** 2017-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410587

## Citation

> US National Institutes of Health, RePORTER application 10410587, Control of aging and age-related diseases by extracellular matrix microenvironment (3R01AG054835-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10410587. Licensed CC0.

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