# Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $495,468

## Abstract

PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is incurable and progressive due to
fibroblast activation, and the formation of scar tissue. Approximately 130,000 Americans suffer from IPF, with
an estimated 50,000 new cases diagnosed each year. Although it is well accepted that myofibroblast
accumulation is a central component of pathogenesis in IPF, the transcriptional program(s) that orchestrate
fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), survival, migration and ECM
organization are poorly defined and represent a significant knowledge gap in the field. Sox9 is a member of the
HMG-box family of transcription factors that are selectively expressed by epithelial progenitor cells to modulate
branching morphogenesis in the lung and the organized deposition of collagen as part of cartilage formation in
multiple organs. However, the role of Sox9 in fibroblast activation has been poorly studied in adult fibrotic lung
diseases. Our new findings have determined that Sox9 is upregulated in lung mesenchymal cells of IPF and
functions as a positive regulator of FMT, myofibroblast survival, migration and ECM production. The loss of
Sox9 expression has attenuated αSMA expression and myofibroblast transformation in mesenchymal cells
isolated from IPF lungs and TGFα model. In support, a recent published study suggest Sox9 upregulation in
patients with chronic liver disease that correlated with fibrosis severity and progression towards cirrhosis.
Taken together, these findings lead us to postulate that Sox9 functions as a positive regulator of FMT,
myofibroblast survival, migration, and ECM in the pathogenesis of pulmonary fibrosis. For this study,
we propose three specific aims: 1) determine mechanisms by which Sox9 induces fibroblast activation; 2)
establish in vivo the role of Sox9-expressing mesenchymal cells in the pathogenesis of pulmonary fibrosis; and
3) identify mechanisms by which Sox9 augments myofibroblast survival and the progression of established and
ongoing pulmonary fibrosis. We will use advanced molecular methods and mouse transgenic approaches,
coupled with detailed biochemical analysis of these Sox9-driven processes in vivo and in vitro. Completion of
the proposed experiments is likely to impart a significant understanding of Sox9-driven fibroblast activation.
The multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and
support future translational studies in IPF. Our approach is innovative due to the generation of novel transgenic
mice to test mesenchymal cell-specific functions of Sox9 in pulmonary fibrosis. The proposed research is
significant in that completion of this study will increase an understanding of the mechanisms causing fibroblast
activation in IPF, which in turn will lead to advanced medical therapies for the treatment and possible cure or
prevention of this debilitating lung disease.

## Key facts

- **NIH application ID:** 10768171
- **Project number:** 7R01HL157176-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Satish K Madala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $495,468
- **Award type:** 7
- **Project period:** 2021-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768171

## Citation

> US National Institutes of Health, RePORTER application 10768171, Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis (7R01HL157176-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10768171. Licensed CC0.

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