Fibroblasts populating fibrotic lesions manifest an unexplained autonomy for growth and survival signals. Fibrotic fibroblasts arise from at least 3 sources: the circulation, resident fibroblasts and the epithelial to mesenchymal transition (EMT). However, the connection between fibroblast origin and autonomous function remains undefined. Here we propose to study lung fibroblasts from patients with Idiopathic Pulmonary Fibrosis and elucidate the mechanism of autonomous function using our discoveries in cancer biology as a guide. In studies of human breast and lung cancer, we discovered that autonomy is conferred by pathological regulation of the translation initiation machinery, designated elF4F. In cancer cells, elF4F serves to integrate growth and survival signals from oncogenes by selectively recruiting ribosomes to groups of transcripts that confer autonomy. Our preliminary data indicate that aberrant activation of elF4F is a property of IFF fibroblasts;that activating elF4F in fibroblasts stimulates cell cycle entry in the absence of growth factors;that mice genetically engineered to lack negative regulators of elF4F have an exaggerated fibrotic response to lung injury;and that activating elF4F in zebrafish ectoderm explants triggers EMT. We therefore hypothesize that pathological translational control contributes to the fibrotic phenotype in IPF by mediating EMT and the emergence of proliferative autonomy. The framework for testing this hypothesis is the post transcriptional operon theory, which posits that recruitment of ribosomes to mRNA is governed by regulatory elements in the transcript 5'and 3'UTR. Acting alone or in concert with trans-acting protein or micro RNA binding partners, RNA regulatory elements provide the instructions for ribosome recruitment. To discover how these ribosome recruitment instructions might be altered in IPF, we propose 2 specific aims: 1) Define the mechanisms linking pathological translational control with IPF fibroblast proliferative autonomy;2) Examine translational control of alveolar epithelial cell EMT and test its relevance to IPF. Our studies will provide the first systems level, genome-wide examination of the fibrotic fibroblast phenotype based on a quantitiative assesment of which mRNA are being actively translated into protein.
If successful, our studies will precisely identify derangements in the gene expression pathway that confer IPF fibroblasts with a pathological phenotype and provide insight into the role of EMT in the genesis of fibroblasts in the IPF lung.This information has the potential to reveal new classes of molecular targets for antifibrotic therapy and unveil new disease-relevant biomarkers for clinical trials.
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