# WT1 REGULATION OF PULMONARY FIBROSIS

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $389,919

## Abstract

PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that is incurable due to the formation of scar
tissue and resultant impaired lung function. Approximately 130,000 Americans suffer from IPF, with an
estimated 50,000 new cases diagnosed each year. Mortality rates from pulmonary fibrosis have increased
significantly in recent years, thereby increasing the demand for pulmonary fibrosis research. Although it is well
accepted that fibrosis is a central component of pathogenesis in IPF, the transcriptional program(s) that
orchestrate fibrotic processes are poorly defined and represent a major knowledge gap in the field. WT1 is a
zinc-finger transcriptional regulator, the function of which has been poorly studied in adult fibrotic lung
diseases. We have recently reported direct clinical evidence of WT1 upregulation in lung mesenchymal cells of
fibrotic lesions in IPF patients. Our new findings have determined that WT1 functions as a positive regulator of
fibroproliferation and ECM production. In support of this, we identified a positive association between the
number of WT1-positive cells and total lung hydroxyproline levels in mouse models of TGFα- and bleomycin-
induced pulmonary fibrosis. Further, inhibition of WT1 expression in vivo was sufficient to attenuate fibrosis in
the lung. Taken together, these findings lead us to postulate that WT1 functions as a positive regulator of
fibroproliferation and ECM production in the pathogenesis of pulmonary fibrosis. For this study, we
propose three specific aims: 1) determine whether reduced WT1 expression is sufficient to attenuate
fibrproliferation and ECM production; 2) determine whether mesenchymal cell-specific expression of WT1 is
critical in the pathogenesis of pulmonary fibrosis; and 3) determine the mechanism by which WT1 promotes
fibroproliferation and ECM production. We will use complementary primary mesenchymal cell culture and
mouse transgenic approaches, coupled with detailed biochemical analysis of these WT1-driven processes in
mouse lung tissues. Completion of the proposed experiments is likely to impart a significant understanding of
WT1-driven pulmonary fibrosis and its transducers, which may be targeted in the future using novel
therapeutics to attenuate pulmonary fibrosis. 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 WT1 functions and its targets involved in the
pathology of pulmonary fibrosis. The proposed research is significant in that completion of this study will
increase an understanding of the mechanisms causing 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:** 10168591
- **Project number:** 5R01HL134801-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Satish K Madala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,919
- **Award type:** 5
- **Project period:** 2017-05-22 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168591

## Citation

> US National Institutes of Health, RePORTER application 10168591, WT1 REGULATION OF PULMONARY FIBROSIS (5R01HL134801-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10168591. Licensed CC0.

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