# Mechanobiology of Lung Fibrosis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $567,924

## Abstract

Project Summary
Pulmonary fibrosis is a progressive and ultimately fatal disease in which ongoing extracellular matrix (ECM)
deposition and feedback biochemical and biomechanical signaling from this matrix promotes disease
progression. Our published and preliminary data demonstrate that YAP and TAZ, transcriptional effectors of
the Hippo pathway, are pivotal regulators of fibroblast activation in IPF, and control both ECM deposition and
stiffening by fibroblasts. However, YAP and TAZ are downstream of multiple pathways, and play critical roles in
multiple lung cell types, complicating efforts to target them therapeutically. Therefore we focus here on
developing a fibroblast-targeted approach to YAP/TAZ inhibition. Specifically, we have identified GPCR
agonism via Gαs-coupled dopamine D1 Receptor (DRD1) as a fibroblast selective approach through which to
inactivate YAP and TAZ. Our in vitro and in vivo preliminary data demonstrate that pharmacologic stimulation
of DRD1 not only attenuates fibroblast activation, but functionally reverses their state from matrix depositing to
matrix degradation and reversal of matrix stiffening. These responses depend on inhibition of YAP/TAZ, as
they are lost in cells expressing constitutively active TAZ mutant protein. Published reports suggest that
endogenous dopaminergic signaling is present in the normal lung; our preliminary data demonstrate that the
dopamine synthetic pathway is transiently depressed during experimental fibrosis in mice, and stably reduced
in the lungs of subjects with IPF. Thus, we posit the central hypothesis that dopamine signaling normally
promotes fibrosis resolution after lung injury, is lost in IPF, and can be selectively targeted by DRD1 agonism
to reverse experimental lung fibrosis. We propose to test this hypothesis in three specific aims, combining in
vitro analysis of dopamine synthesis by lung epithelial cells and dopaminergic signaling effects on lung
fibroblast function, as well as in vivo analysis of experimental fibrosis in mice in which endogenous dopamine
production is lost, or exogenously augmented pharmacologically. Together the proposed studies will delineate
a novel receptor mediated mechanism by which fibroblast can be switched from fibrosis promoting to fibrosis
resolving states, test the therapeutic efficacy of exogenous targeting of this pathway in durable fibrosis models,
and explore whether the endogenous activity of this pathway normally protects from and resolves progressive
fibrosis, and is lost in human disease.

## Key facts

- **NIH application ID:** 10160943
- **Project number:** 5R01HL092961-11
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Daniel J. Tschumperlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $567,924
- **Award type:** 5
- **Project period:** 2009-08-06 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160943

## Citation

> US National Institutes of Health, RePORTER application 10160943, Mechanobiology of Lung Fibrosis (5R01HL092961-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10160943. Licensed CC0.

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