Woodcock, HV; (2017) The role of PI3K/mTOR signalling in the pathogenesis of Idiopathic Pulmonary Fibrosis. Doctoral thesis , UCL (University College London).

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Abstract

Idiopathic pulmonary fibrosis (IPF) is characterised by the uncontrolled deposition of type 1 collagen rich extracellular matrix by myofibroblasts, leading to distortion of tissue architecture, impairment of gas exchange, and respiratory failure. The profibrotic cytokine TGF-β is central to this process. Evidence suggests that PI3K/mTOR signalling downstream of TGF-β may be central to the key cellular processes that drive fibrotic pathology. GSK2126458 is a combined PI3K/mTOR inhibitor, which has been shown to prevent functional responses to TGF-β in human lung fibroblasts and is currently being evaluated in a proof-of-mechanism clinical trial in IPF. The present study identifies that delayed and sustained induction of mTOR signalling mediates the late peak in pro-fibrotic gene expression in response to TGF-β. Accordingly, active-site mTOR inhibition has pronounced inhibitory effects on collagen biosynthesis and myofibroblast differentiation of primary human lung fibroblasts (pHLFs). The induction of mTOR signalling in response to TGF-β is dependent on the canonical Smad pathway. In addition, TGF-β induced mTOR signalling is demonstrated to be independent of PI3K/Akt activity, suggesting that mTOR is not activated through the prototypical linear PI3K/Akt/mTOR signalling axis downstream of TGF-β. mTOR is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, which have differential sensitivities to rapamycin. The present study identifies that rapamycin-resistant mTOR signalling is critical for TGF-β induced profibrotic gene expression in pHLFs. Furthermore, knockout of critical mTOR complex subunits in mouse embryonic fibroblasts demonstrates that mTORC2 is an important regulator of pro-fibrotic gene expression. Taken together, this work identifies mTOR as a critical pro-fibrotic signalling node downstream of TGF-β. Selective mTOR inhibition is a promising therapeutic strategy for fibrotic disease.

Type:	Thesis (Doctoral)
Title:	The role of PI3K/mTOR signalling in the pathogenesis of Idiopathic Pulmonary Fibrosis
Event:	UCL (University College London)
Language:	English
UCL classification:	UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI:	https://discovery.ucl.ac.uk/id/eprint/1536311

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