# The role of matrix-bound microvesicles in alcohol-related liver disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $497,269

## Abstract

Alcohol-related liver disease (ALD) is a prevalent clinical problem, with many knowledge gaps in the
pathogenesis of ALD, including the role and regulation of inflammatory and tissue reactions. Our overarching
goal is to identify key new players in alcohol-mediated effects on development and progression of liver
damage and fibrosis that could translate to targeted therapies. The extracellular matrix (ECM) and ECM
dyshomeostasis are known to be important in ALD. ECM is produced by resident cells in the tissue/organ and
contains a diverse range of components that create a dynamic and responsive microenvironment that regulates
cell and tissue homeostasis. Our previous work demonstrated diverse qualitative and quantitative alterations to
hepatic ECM during experimental ALD. In toto, alterations to the hepatic ECM are mediated not only by changes
in ECM production, but also by changes in ECM degradation. We and others have demonstrated that even acute
liver injury causes robust hepatic ECM changes. ECM also represents a potent reservoir of cell-signaling
molecules that regulate cell behavior, determine cell phenotype and cell secretome, as well as influence
inflammatory tissue responses. Numerous examples exist of cells dramatically changing their structural and
functional phenotype when exposed to ECM different from their existing (normal or abnormal) ECM. By
extension, changes to and/or altered turnover of hepatic ECM have potential to drive phenotypic changes in
disease pathogenesis and progression. Work from our group shows that a major source of signaling molecules
in ECM resides within matrix bound nanovesicles (MBV). MBV are nanometer-sized, membranous vesicles
uniquely-bound within the ECM network. MBV contain and protect biologically active signaling molecules
(miRNAs/proteins), and are known to play a role in immunomodulation, stem/progenitor cell differentiation, and
maintenance of structurally normal and functional tissues. MBV likely play a fundamental role in tissue and organ
organization across species and a regulatory role in the tissue response to injury. Our exciting preliminary studies
show alcohol exposure dramatically alters hepatic MBV proteome and RNA/miRNA content. Similar changes are
also seen in liver MBV isolated from ALD human explant livers vs liver MBV from non-ALD patients. We also
show that liver MBV from alcohol-fed mice have differential effects on macrophage polarization and activation.
Most importantly our preliminary findings suggest exogenous administration of MBV can significantly reduce
alcohol-associated liver damage and inflammation. We hypothesize that MBV act not only as tissue
biomarkers of ALD but are also important in regulating pathogenesis and disease progression. We will
test this hypothesis via the following Specific Aims: 1. To analyze liver MBV biology in ALD.; 2. To understand
mechanisms of liver MBV effects in ALD; 3. To test the ability of MBV to treat experimental ALD. Impact:
Successful complet...

## Key facts

- **NIH application ID:** 10840258
- **Project number:** 5R01AA030007-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gavin E Arteel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $497,269
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840258

## Citation

> US National Institutes of Health, RePORTER application 10840258, The role of matrix-bound microvesicles in alcohol-related liver disease (5R01AA030007-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10840258. Licensed CC0.

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