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Principal Investigator: Satish K Madala
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $449,264
Funding agency: National Heart Lung and Blood Institute
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 fibroproliferation, fibroblast-to-myofibroblast transformation (FMT), survival, and
collagen production are poorly defined and represent a significant 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 fibroblasts of IPF and mouse models of
severe fibrotic lung disease. Recently published studies from our lab highlight that WT1-positive fibroblasts
play a pathogenic role in pulmonary fibrosis. In this regard, we generated fibroblast-specific WT1 knockout and
overexpression mice to investigate mechanisms and develop new therapeutic interventions against WT1-
driven pulmonary fibrosis. The focus of this application is to identify WT1-driven gene targets that are
druggable to prevent fibroblast activation and pulmonary fibrosis. Our efforts to identify key targets of WT1
involved in fibroblast activation have led us to identify several anti-apoptotic genes, MYCN, and PLK1 as
important mediators of WT1-induced pulmonary fibrosis. In support, we observed significant increases in
MYCN and PLK1 by WT1 in lung fibroblasts of IPF and mouse models of pulmonary fibrosis. Importantly, we
have identified a potent inhibitor of PLK1 called Volasertib (BI 6727; Phase I/II compound), as a lead small
molecule inhibitor that can block a feed-forward loop of the MYCN-PLK1 axis to attenuate WT1-driven
fibroblast activation. Together, these findings lead us to postulate that WT1 functions as a positive
regulator of anti-apoptotic genes (BCL3 and BCL2L1), and the MYCN-PLK1 axis and that these factors
are involved in fibroblast activation and pulmonary fibrosis. For this study, we propose three specific
aims: 1) determine mechanisms by which WT1 inhibits apoptotic clearance in fibroblasts during the
progressive expansion of fibrotic lesions; 2) determine mechanisms underlying WT1-driven the MYCN-PLK1
axis in fibroproliferation, FMT, and ECM production, and 3) test the therapeutic potential of volasertib therapy
compared to FDA-approved anti-fibrotic therapies using two alternative mouse models of severe fibrotic lung
disease. We will use advanced molecular methods and mouse transgenic approaches, coupled with detailed
biochemical analysis of these WT1-driven processes in vivo and in vitro. Completion of the proposed
experiments is likely to impart a significant understanding of WT1-driven fibroblast activation. The
multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and offers
insight into new and highly needed treatments in IPF.
Terms: <21+ years old><Adult><Adult Human><American><Apoptotic><Area><Assay><Attenuated><B-Cell CLL/Lymphoma 3 Gene><B-cell lymphoma-extra large><BCL-XL><BCL2-Like 1><BCL2-Related Gene><BCL2-Related Protein, Long Isoform><BCL2-Related Protein, Short Isoform><BCL2L1><BCL2L1 gene><BCL3><BCL3 gene><BCL4><BCLX><BCLXL><BCLXS><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biochemical><Biological Assay><Bleo><Bleomycin><Body Tissues><Cell Body><Cell-Extracellular Matrix><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Cicatrix><Clinical><Collagen><Coupled><D19S38><Data><Deposit><Deposition><Diagnosis><Disabling><Disease><Disorder><ECM><Epidermal Growth Factor-Related Transforming Growth Factor><Extracellular Matrix><FDA approved><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Fibrotic lesions in lung><Funding><Gene Targeting><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Goals><Impairment><In Vitro><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Lead><Lesion><Luciferase Immunologic><Luciferases><Lung><Lung Respiratory System><Lung Tissue Fibrosis><Lung scar><Lung tissue scar><MYCN><MYCN gene><Mediator><Methods><Mice><Mice Mammals><Molecular><Murine><Mus><Myofibroblast><NMYC><NMYC Gene><Null Mouse><Ofev><PLK Gene><PLK1><PLK1 gene><Pathogenesis><Pathogenicity><Pathologic><Pathologic Processes><Pathological Processes><Patients><Pb element><Peripheral><Phase><Play><Polo-Like Kinase><Preventative intervention><Process><Production><Publishing><Pulmonary Fibrosis><Pulmonary Pathology><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulation><Reporting><Resolution><Role><STPK13><Scarring at the lung><Scarring in the lung><Scars><Serine/Threonine Protein Kinase 13><TGF A><TGF-alpha><TGF-α><TGFalpha><TGFα><Testing><Therapeutic Intervention><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transforming Growth Factor alpha><Transgenic Mice><Up-Regulation><Upregulation><WAGR><WT1><WT1 Gene Product><WT1 Protein><WT1 gene><WT33><Wilms Tumor 1><Wilms tumor suppressor WT1><Work><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><adulthood><antifibrotic agent><antifibrotic medication><antifibrotic therapy><antifibrotic treatment><attenuate><attenuates><chromatin immunoprecipitation-sequencing><diffuse interstitial pulmonary fibrosis><drug candidate><druggable target><experiment><experimental research><experimental study><experiments><fibrosis in the lung><fibrotic lung><fibrotic lung disease><fibrotic pulmonary disease><heavy metal Pb><heavy metal lead><idiopathic pulmonary fibrosis><improved><in vivo><inhibitor><innovate><innovation><innovative><insight><intervention for prevention><intervention therapy><loss of function><lung fibrosis><lung function><lung lesion><lung pathology><mouse model><multidisciplinary><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><nintedanib><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><overexpress><overexpression><pharmacologic><polo-like kinase 1><prevent><preventing><prevention intervention><preventional intervention strategy><preventive intervention><programs><promoter><promotor><pulmonary><pulmonary function><pulmonary lesion><resolutions><small molecular inhibitor><small molecule inhibitor><social role><therapeutic evaluation><therapeutic testing><transcription factor><transcriptome sequencing><transcriptomic sequencing><treatment strategy>