Monoclonal Antibody Targeting Pear1 for Pulmonary Fibrosis Therapy [bulk RNA-seq]

ABSTRACT: Pulmonary fibrosis (PF) is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts (FBs) play a central role in progression of PF. Here we report that platelet endothelial aggregation receptor 1 (Pear1) in FBs is a new molecular target for PF therapy. Pear1 deficiency spontaneously caused respiratory function decline and alveolar collagens accumulation in old mice. The degree of PF and mortality induced by bleomycin were significantly enhanced in Pear1 deficient mice. FB Mesenchyme-specific Pear1 deficiency aggravated bleomycin-induced PF, confirming that Pear1 modulates PF progression probably byvia regulation of FBs function. Single cell RNA-seq analysis of pulmonary FB and functional enrichment analysis revealed drastic expansion of Aactivated- FB clusters and enrichment of activated FB marker genes in extracellular matrix (ECM) development and pulmonary fibrosis in Pear1-/- fibrotic lungs. CD140+ bulk tissue RNA-seq analysis further confirmed that multiple mesenchyme development pathways especially epithelial mesenchymal transition (EMT) are enriched with up-regulated genes involving FB mediated ECM organization and development in in Pear1-/- fibrotic lungs. We further found that Pear1 associated with Protein Phosphatase 1 to suppress fibrotic factors such as TGFß, FGF or PDGF-induced intracellular signalling and FB activation. Intratracheal aerosolization of monoclonal antibody activating Pear1 greatly ameliorates PF in both wild-type mice and Pear1-humanized mice, suggesting that targeting Pear1 may serve as a new therapeutic strategy for PFand significantly improves their survival rate.

ORGANISM(S): Mus musculus

PROVIDER: GSE183657 | GEO | 2021/10/20

REPOSITORIES: GEO