# The Role of Matrix Rigidity and Hepatocyte Mechanotransduction in Fibrotic Liver Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $356,625

## Abstract

PROJECT SUMMARY
Liver fibrosis, and ultimately cirrhosis, is the final common pathway of chronic liver diseases induced by any
etiology. Liver failure due to cirrhosis is the 12th leading cause of death by disease in the United States and
there is no effective current treatment other than liver transplantation. One hallmark of liver cirrhosis is that the
liver extracellular matrix becomes stiffer, but how the stiffened microenvironment causes hepatocyte
dysfunction is not completely understood. Our proposed research addresses this gap in knowledge and is
designed to deliver data that will lead to tangible advances in the treatment of liver cirrhosis, which may include
development of 1) novel therapies that maintain adequate liver function in patients with progressive fibrotic liver
disease, 2) clinical prognostic models that predict which patients with resolving fibrosis may regain sufficient
hepatic function, and 3) highly functional tissue-engineered liver constructs for tissue replacement therapy in
patients with end-stage liver insufficiency. Our preliminary studies show that hepatocytes are exquisitely
responsive to the mechanical cues of extracellular matrix tuned to the stiffness of fibrotic livers, and that the
induced downstream signaling pathways (i.e. mechanotransduction) directly inhibit hepatocyte function. Using
a multi-disciplinary cross-modality approach, we propose to further delineate the mechanism of how a stiffened
microenvironment induces hepatocyte dysfunction and its clinical applicability. These scientific objectives will
be achieved first, by determining the key molecular players that translate mechanical cues into intracellular
signals that inhibit hepatocyte function using genetically engineered mouse models with tissue-specific and
temporally-induced expression of key mechanotransduction molecules. Subsequently, we propose to verify the
clinical relevance of these molecular mechanisms by characterizing matrix rigidity at the microscale level in
normal and cirrhotic human livers as determined by atomic force microscopy, in conjunction with single-cell
gene expression analysis. Finally, we propose to test whether the relationship between microenvironment
rigidity and hepatocyte function may be recapitulated in complex tissue-engineered liver constructs that are
produced by three-dimensional bioprinting ex vivo and tuned to the stiffness of normal or fibrotic human liver.
The proposed research is conceptually innovative because, instead of attempting to therapeutically target the
process of fibrosis, we aim to understand the hepatocyte response to fibrosis, thereby prompting new
approaches to treat and prognosticate chronic liver disease that focus on modulating the hepatocyte response
to the fibrotic stimulus. It is, in the end, liver functional failure that causes death from liver disease, and not
necessarily the process of fibrosis in itself. Results from this proposed study will authoritatively define the role
of matr...

## Key facts

- **NIH application ID:** 10200030
- **Project number:** 5R01DK114311-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** TAMMY T CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,625
- **Award type:** 5
- **Project period:** 2017-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200030

## Citation

> US National Institutes of Health, RePORTER application 10200030, The Role of Matrix Rigidity and Hepatocyte Mechanotransduction in Fibrotic Liver Disease (5R01DK114311-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200030. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*