# Pathological consequences of altered tissue mechanics in fibrosis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $491,086

## Abstract

PROJECT SUMMARY
Cells and tissues are mechanosensitive. Many tissues, including the liver, are subjected to mechanical stresses
and deformed at varying magnitudes and rates that can be altered in disease. When the mechanical properties
of tissues change, as in fibrosis, or when stresses are abnormal, as with increased vascular pressures, cells are
abnormally deformed, with resulting changes in cellular function that can initiate or augment disease. The design
principles that determine tissue mechanics, however, are largely unknown. While the viscoelasticity of
crosslinked semi-flexible polymer networks (ubiquitous in both the internal cytoskeleton and the extracellular
matrix (ECM)) is generally assumed to dominate tissue mechanics, the mechanical responses of soft tissues
and semiflexible polymer gels are the opposite of each other in many respects. Three-dimensional tissues stiffen
in compression and mildly soften in extension, whereas semiflexible biopolymer networks soften in compression
and stiffen in extension. Our overall goal is to use experimental and theoretical studies to determine how the
presence of cells within fibrous networks can explain the viscoelastic response of intact tissues and thereby help
explain how changes in the properties of either the matrix or the cells can alter the tissue mechanical properties
that occur in disease.
We propose to expand the knowledge generated during the first three years of funding of this proposal to further
study the role of fibrous matrices in tissue and cell mechanics. Specifically, we will develop a more detailed
understanding of the relationship between fibrous networks and cell and tissue responses to cell-
generated or externally applied forces. This work will capitalize on our expertise and preliminary work on a
model tissue, the normal and fibrotic liver, but the findings will be generally applicable to organs and soft tissues
in the body. We will explore the role of complex fibrous networks in tissue behavior at various time and length
scales, basing our work on the hypothesis that fibrous networks are critical determinants of tissue mechanics
and of the behavior of cells within tissues. The three specific aims are to: 1) Define the role of the fibrous
interstitial matrix of tissues in the mechano-responsiveness of real and model tissues and develop a multiaxial
mechanical model of a simple tissue; 2) Determine the role of free and proteoglycan-bound GAGs in collagen
fibrous networks and tissue mechanics; and 3) Define mechanisms that determine the plasticity (permanence)
of tissue-scale matrix remodeling.
For all aims, we will carry out both experimental and theoretical work, with the ultimate goal of understanding
cell and tissue behavior in different physiologically-relevant matrix and mechanical environments. These studies
will enable us to better understand the deleterious changes in tissue mechanics that are increasingly
documented to contribute to (rather than simply result from...

## Key facts

- **NIH application ID:** 10240476
- **Project number:** 5R01EB017753-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Paul A Janmey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,086
- **Award type:** 5
- **Project period:** 2014-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240476

## Citation

> US National Institutes of Health, RePORTER application 10240476, Pathological consequences of altered tissue mechanics in fibrosis (5R01EB017753-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10240476. Licensed CC0.

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