# Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2020 · $188,170

## Abstract

Project Summary
Liver fibrosis/cirrhosis is the 14th leading cause of death worldwide. Despite the prevalence of this disease,
there are no drugs to treat liver fibrosis/cirrhosis. Several landmark clinical studies have demonstrated that
fibrosis, and even cirrhosis, are reversible in patients. In animal models, during regression of fibrosis, disease
causing, “pro-fibrotic macrophages” differentiate into “pro-resolving macrophages”. These macrophages
produce matrix metalloproteinases (MMPs) that remove excess extracellular matrix and produce mediators
that terminate matrix production by “activated” hepatic stellate cells, the primary matrix producing cell in the
liver. The studies proposed in this application aim to exploit the phenotypic plasticity of pro-fibrotic
macrophages and identify chemicals/drugs that stimulate their conversion into pro-resolving macrophages.
Towards this goal, we have developed a primary screening assay that utilizes high-content imaging to detect
macrophage phenotypic transition in a 384 well format. With this assay, we propose to screen a library of 3,000
compounds of known mechanism of action to identify drugs for repurposing as macrophage phenotypic
modulators with anti-fibrotic properties. We will screen an additional library of 23,000 compounds with
unknown activities to identify novel anti-fibrotics. Positive hits from these screens will be further characterized
by using the Nanostring assay, in a medium throughput format, to quantify several macrophage phenotype-
specific mRNAs. Top hits from this secondary screen will be further evaluated in biological assays for anti-
fibrotic activity. Collectively, these studies have the potential to identify novel anti-fibrotics that not only limit
further fibrosis development but stimulate fibrosis reversal by triggering the conversion of pro-fibrotic
macrophages into pro-resolving macrophages. Identification of compounds with this novel activity has the
potential to tremendously impact treatment of liver fibrosis/cirrhosis.

## Key facts

- **NIH application ID:** 10072111
- **Project number:** 1R21AI152554-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Bryan L Copple
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,170
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072111

## Citation

> US National Institutes of Health, RePORTER application 10072111, Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment (1R21AI152554-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10072111. Licensed CC0.

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