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Translational Dysregulation Driving Mesenchymal Cell Fibrogenic Transformation and Chronic Lung Allograft Dysfunction

翻译失调驱动间充质细胞纤维化转化和慢性同种异体肺移植功能障碍

基本信息

批准号：
10374872
负责人：
Vibha N Lama
金额：
$ 59.54万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374872
关键词：
Airway Fibrosis Allografting Autocrine Communication Automobile Driving Bronchiolitis Obliterans Cause of Death Cells Chronic Clinical Collagen Cytometry Data Defect Deposition Development Eukaryotic Initiation Factors Evaluation Event FRAP1 gene Failure Fibrosis Functional disorder Future Genetic Histologic Human Immune Immunodeficient Mouse Immunosuppression In Vitro Inflammatory Intervention Investigation Knock-out Lesion Life Light Lipids Lung Lung Transplantation Lysophospholipase Malignant Neoplasms Mesenchymal Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Mus Mutant Strains Mice Oncogenic Oral Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Play Procedures Protein Kinase Protein-Serine-Threonine Kinases Proteins Proteomics Publishing Regulation Resistance Role Savings Scheme Serine Signal Pathway Signal Transduction Solid Syndrome Testing Therapeutic Therapeutic Trials Transcriptional Activation Transgenic Mice Translational Activation Translations Transplant Recipients Transplantation Work autocrine beta catenin cytokine fibrogenesis graft failure improved in vitro activity in vivo inflammatory milieu inhibitor lung allograft metaplastic cell transformation new therapeutic target novel novel therapeutic intervention post-transplant preclinical study prevent programs protein expression pulmonary function ribosome profiling small molecule transplant model tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT 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.

项目总结/文摘