Dataset Information

Role of mTOR in regulating the extra cellular matrix

ABSTRACT: Explored the potential role of mTOR in regulating the extra cellular matrix of TGF-b1-stimulated IPF fibroblasts grown under macromolecular crowding conditions in the presence of either CZ415 or rapamycin

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Fibroblast Of Lung

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD010164 | Pride | 2018-11-04

REPOSITORIES: Pride

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Publications

The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.

Woodcock Hannah V HV Eley Jessica D JD Guillotin Delphine D Platé Manuela M Nanthakumar Carmel B CB Martufi Matteo M Peace Simon S Joberty Gerard G Poeckel Daniel D Good Robert B RB Taylor Adam R AR Zinn Nico N Redding Matthew M Forty Ellen J EJ Hynds Robert E RE Swanton Charles C Karsdal Morten M Maher Toby M TM Fisher Andrew A Bergamini Giovanna G Marshall Richard P RP Blanchard Andy D AD Mercer Paul F PF Chambers Rachel C RC

Nature communications 20190102 1

Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β<sub>1</sub> stimulated collagen synthesis in human lung fibroblasts, whereas canoni ...[more]

PMID: 30602778

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

Dataset Information

Role of mTOR in regulating the extra cellular matrix

Publications

The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.

Similar Datasets

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