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 TGF?- 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.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is an incurable, disabling, and often fatal disease characterized by the distribution of fibrotic lesions predominantly in the peripheral areas of the lung. Validation of the functional association between WT1-driven transcriptional programs and fibroblast phenotypes in the pathology of IPF, may provide new targets for clinical interventions of IPF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Lin, Sara
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Cincinnati Children's Hospital Medical Center
United States
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