Chronic lung allograft dysfunction (CLAD) marked by progressive graft failure develops in 50% of lung transplant recipients by 5 years and is the major cause of poor-long term outcomes after this life-saving procedure. Predominant clinical presentation is development of persistent obstructive ventilatory defect termed bronchiolitis obliterans syndrome (BOS) resulting from fibrotic obliteration of the small airways or bronchiolitis obliterans (BO). Graft-resident mesenchymal cells (MCs) play a key role in pathogenesis of BO and our recent studies demonstrate that autonomous activation of MCs marked by increased matrix deposition and stable activation of pro-fibrotic pathways is a key driver of the allograft fibrosis and dysfunction. Various signaling pathways were shown to converge at the level of eukaryotic translation initiation factor 4E (eIF4E) to regulate key fibrotic functions like collagen I expression in BOS MCs. In this application we aim to investigate the role of MAP kinase? interacting serine/threonine kinase (MNK) induced direct phosphorylation of eIF4E at serine 209 in maintaining fibrogenic transformation of BOS MCs and determine the contribution of MNK/eIF4E pathway to pathogenesis of BO post-transplantation. MNK kinase induced phosphorylation of eIF4E at serine 209 has been demonstrated to be critical in promoting its oncogenic potential but has not been investigated in the context of fibrosis. Our preliminary data demonstrates a constitutively higher eIF4E phosphorylation at Serine209 in MCs from patients with BOS. eIF4E phospho-S209 was found to be critical in regulating key fibrogenic protein autotaxin and sustaining the fibrotic functions of BOS MCs. MNK signaling was upregulated in BOS cells and genetic or pharmacologic targeting of MNK activity inhibited eIF4E phospho-S209 and fibrotic functions of BOS MCs in vitro. In vivo treatment with MNK inhibitor eFT-508 was found to decrease allograft fibrosis in orthotopic murine lung transplant model.
In Aim 1 we will utilize MCs derived from patients BOS to dissect the molecular mechanisms via which eIF4E Ser209 phosphorylation contributes to fibrogenic transformation of human lung MCs.
Aim 2 will investigate the role of MNK/eIF4E signaling in development of BO in a murine orthotopic lung transplant model of BO by utilizing MNK1/2 Knockout and eIF4ES209A/A mutant mice to target MNK/eIF4E S209 in donor lungs. Preclinical studies of a novel orally available MNK1/2 inhibitor eFT508 in murine orthotopic whole lung transplant BO model with assessment of fibrotic and immune/inflammatory endpoints proposed in Aim 3 will lay the background for future human therapeutic trials. Together these studies will shed novel light on the role of MNK/eIF4E Ser209 phosphorylation in fibrotic activation of MCs and test its potential as an attractive target for halting fibrogenic progression and development of CLAD.
This application explores a novel signaling pathway of fibrogenic mesenchymal cell activation. These studies will be the first to investigate the role of MNK/eIF4E signaling pathway in lung allograft fibrogenesis. Pre-clinical studies of a novel orally available MNK1/2 inhibitor eFT508 in murine orthotopic whole lung transplant BO model will lay the background for future human therapeutic trials.
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