# Targeting durotaxis in lung injury and fibrosis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $559,550

## Abstract

Project Summary/Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease characterized by progressive scarring of the lungs,
ultimately impeding the ability to breathe. Pathological recruitment of fibroblasts to sites of tissue injury and
subsequent activation into scar-forming myofibroblasts are critical steps in the development and progression of
pulmonary fibrosis. Accordingly, the identification of the molecular mediators directing fibroblast recruitment
and myofibroblast activation, will not only further enhance our understanding of the pathogenesis of lung
fibrosis, but also provide rational therapeutic targets for novel anti-fibrotic therapies. We and others have
recently shown that increased matrix stiffness in fibrotic lungs promotes mechano-activation of fibroblasts.
Further, matrix stiffness amplifies tissue fibrosis by locking stiffness-activated myofibroblasts on a mechanical
positive feedback loop, by not fully understood mechanisms. We have recent evidence that matrix stiffness
gradients produced in fibrotic lung tissues promote fibroblast recruitment to sites of tissue injury via durotaxis –
the directed migration of cells from regions of lower to higher stiffness, which occurs independently of diffusible
chemoattractants or substrate-bound haptotactic cues. As fibroblast “durotax” to regions of increased stiffness,
the stiffness of these regions would drive the arriving fibroblasts to differentiate into myofibroblasts.
Consequently, the central hypotheses of this proposal are that: (1) fibroblasts are recruited to sites of focal
tissue injury via durotaxis, a mechanism in which cells migrate up stiffness gradients independently of
chemotactic signals; and (2) that inhibition of fibroblast durotaxis has the potential to be a new therapeutic
strategy for IPF. The studies proposed in this application are designed to visualize fibroblast durotaxis in vivo,
to define molecular mechanisms of fibroblast durotaxis and to develop novel therapeutic strategies to inhibit
durotaxis. Specifically, we propose: (1) To image fibroblast durotaxis ex vivo using multiphoton microscopy in
precision cut lung slices and to investigate the therapeutic efficacy of targeting fibroblast durotaxis in vivo in a
mouse model of lung fibrosis by inhibiting the mechanosensitive FAK/Paxillin pathway; (2) To define
mechanisms by which the αvβ3/FAK/Paxillin pathway regulates matrix rigidity sensing and durotaxis in IPF
fibroblasts. We will investigate both biochemical and biophysical regulators of αvβ3 integrin and their role in
fibroblast durotaxis; and (3) To define mechanisms by which actin-microtubule crosstalk mediates fibroblast
durotaxis. Specifically, we will investigate mechanisms by which α-TAT1-mediated microtubule acetylation
controls dynamic recycling of αvβ3/FAK/Paxillin complexes in durotactic cells. We will also test the role of
αTAT-1 in fibroblast durotaxis and pulmonary fibrosis in vivo in the bleomycin model of lung fibrosis, using
...

## Key facts

- **NIH application ID:** 10364927
- **Project number:** 1R01HL157384-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Benjamin David Medoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,550
- **Award type:** 1
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364927

## Citation

> US National Institutes of Health, RePORTER application 10364927, Targeting durotaxis in lung injury and fibrosis (1R01HL157384-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10364927. Licensed CC0.

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