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MicroRNAs und epitheliale-mesenchymale Interaktion im Kontext einer Lungenfibrose

Fachliche Zuordnung Entwicklungsbiologie
Förderung Förderung von 2018 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 406538808
 
Erstellungsjahr 2024

Zusammenfassung der Projektergebnisse

Idiopathic Pulmonary Fibrosis (IPF), the most common and lethal interstitial lung disease of unknown etiology, is a highly morbid progressive and irreversible disorder. IPF is a disease associated with aging and as such its incidence is anticipated to gradually increase as the proportion of the population of older adults increases. While different treatments are available to manage the disorder (ie: nintedanib and perfenidone) and several newer therapeutic options are being studied, there is no cure for IPF. Ultimately, some affected individuals will require a lung transplant. In this context, there is an urgent need for a better understanding of the underlying cellular and molecular mechanisms responsible for IPF. The pathogenesis of IPF is complex and largely unknown. Current hypotheses suggest that microrepetitive injury of unknown origin to pulmonary epithelial cells in the aging lung results in ineffective repair with subsequent fibrogenesis. Myofibroblasts (MYFs) appear as the main final pathological actor, notably by secreting important amount of Extracellular Matrix components thus promoting lung tissue stiffening. Once the MYF focus is initiated, complex epithelial–mesenchymal interactions including direct contacts and soluble mediators contribute to disease progression. Multiple biological pathways, often involved in lung development have been reported, including TGF-beta, suggesting that embryonic signaling pathways involved in epithelium/ mesenchymal communication and epithelial cell plasticity are aberrantly reactivated in IPF. Recent evidence from our teams has emphasized the roles played by microRNAs (miRNAs) in regulating these signaling pathways in lung mesenchyme during development or during the fibrogenic response to tissue injury. The main objective of the FIBROMIRs project was to investigate the role of specific FibromiRs during both lung fibrosis formation and resolution using in vivo loss of function approaches, to characterize their targets and to evaluate the therapeutic value of inhibitors in a preclinical model of lung fibrosis. The strength of the project relies on the state-of the art investigation of lung phenotype in lung fibrosis model including lineage-tracing approaches, miRNA target identification using a combination of experimental and in silico approaches, access to patient samples and validated preclinical mouse / cell models as well as genomics approaches (including single-cell technologies). The project is divided into three scientific Aims: i) to investigate the expression of miRNAs at different stages of fibrosis formation and resolution in mouse models as well as in fibroblasts subpopulations purified from fibrotic mice or IPF lungs and stimulated with pro- or anti-fibrotic treatments ; ii) to characterize the precise function of these miRNAs in lung fibrogenesis and fibrosis resolution using in vivo loss of function approaches and single cell transcriptomics ; iii) to determine the therapeutic value of targeting these miRNAs in lung fibrosis preclinical model as well as on the phenotype of IPF lung-derived fibroblasts. We have notably identified a cluster of three profibrotic mature miRNAs, which influence the TGF-β signaling leading to MYF activation. A pre-clinical study using a lung fibrosis mouse model has demonstrated the anti-fibrotic potential of different strategies aiming at interfering with this cluster or with these individual “FibromiRs”. Altogether, these results provide preclinical proof-of-concept for FibromiRs targeting as a new approach to treat lethal pulmonary fibrosis. These data have been strengthened in IPF patients-derived fibroblasts with these anti-FibromiRs showing reduced basal and TGF-β-induced expression levels of fibrotic markers.

Projektbezogene Publikationen (Auswahl)

 
 

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