# Biophysical regulation of macrophage function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $578,697

## Abstract

PROJECT SUMMARY
Macrophages are central regulators of inflammation and tissue healing following injury or
infection, and during disease. While much is known about how soluble, biochemical factors in the
environment regulate macrophage function, less is known about how biophysical cues regulate
their response, despite the fact that these cells exist within solid tissues that are rich in mechanical
cues. Furthermore, many diseases in which macrophages are involved, such as cancer and
fibrosis, are characterized by changes in tissue biophysical properties. Our previous work
demonstrated that adhesion to soft extracellular matrix hydrogels inhibits macrophage
inflammatory activation. In preliminary work, we found that matrix rigidity influences the
localization of YAP, a transcriptional co-factor involved in cell proliferation, organ size control, and
cancer, but with previously undescribed role in macrophage activation. Adhesion to stiff
substrates leads to YAP nuclear localization, which appears to prime macrophages for a potent
inflammatory response. In addition, cytoskeletal polymerization and the mechanically-activated
and calcium-permeable ion channel Piezo1 appear to be involved in YAP nuclear localization and
inflammatory activation. In this study, we propose to investigate the molecular mechanisms
underlying YAP signaling and Piezo1 activity in the macrophage response within different stiffness
environments. In Aim 1, we will examine the effect of stiffness on cytoskeletal remodeling and
associated signaling pathways on YAP activity. In Aim 2, we will probe the role of Piezo1-mediated
calcium activity in stiffness sensing, YAP signaling, and macrophage function. Finally, in Aim 3,
we will investigate the role of YAP and Piezo1 on macrophage-mediated wound healing in vivo
using a murine subcutaneous biomaterial implant model. An improved fundamental
understanding of how macrophages sense their mechanical environment may lead to new
immunomodulatory strategies that control macrophage function during disease.

## Key facts

- **NIH application ID:** 10268232
- **Project number:** 5R01AI151301-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Wendy Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $578,697
- **Award type:** 5
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10268232

## Citation

> US National Institutes of Health, RePORTER application 10268232, Biophysical regulation of macrophage function (5R01AI151301-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10268232. Licensed CC0.

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