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

• 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
• 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

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.

项目摘要/摘要 慢性肺同种异体功能障碍（CLAD）在50％的肺移植中出现了以进行性移植衰竭的标志 接收者到5年，是挽救生​​命程序后长期术语不佳的主要原因。 主要的临床表现是持续性阻塞性通风缺陷的持续发展称为细支气管炎 小型气道或支气管炎闭塞（BO）引起的闭塞综合征（BOS）。 移植物居住的间充质细胞（MCS）在BO的发病机理和我们最近的研究中起关键作用 证明MC的自主激活以增加的基质沉积和稳定激活为标志 纤维化途径是同种异体纤维化的关键驱动力和功能障碍。 显示以在真核翻译起始因子4E（EIF4E）的水平上收敛到常规的纤维纤维动物 诸如BOS MC中的胶原蛋白表达之类的功能。 相互作用的丝氨酸/苏氨酸激酶（MNK）在维持丝氨酸209处诱导EIF4E的直接磷酸化 BOS MC的纤维化转化，并确定MNK/EIF4E对发病机理的贡献 已证明了MNK激酶在丝氨酸209处诱导的phoss磷酸化 至关重要的是促进其致癌潜力，但在纤维化的背景下尚未进行研究 初步数据表明，患者的MCS中有丝氨酸的组成性高EIF4E磷酸化。 与BOS相关。 维持BOS MC的纤维化功能。 MNK活性的药理学靶向抑制EIF4E Phospho-S209和Fispho-S209和Fispho-S209和Fispho-S209和Fispho-S209以及Fispho-S209以及Fispho-S209和Fispho-S209和Fispho-S209和Fispho-S209以及Fispho-S209和Fispho-S209和Fispho-S209和Fispho-S209和Fispho-S209和Fispho-S209和纤维化的FUS MCS 通过MNK抑制剂EFT-508的体内治疗可降低原位鼠的全球纤维化 AIM 1中的肺移植模型。 EIF4E Ser209磷酸化的机制有助于人类lungg的纤维化转化 MCS。 通过利用MNK1/2敲除和EIF4ES209A/A突变小鼠的移植模型来靶向MNK/EIF4E S209 在供应的ORALE的临床前研究中，可避免的MNK1/2 肺移植BO模型，评估AIM 3中支撑的纤维化和免疫/炎症终点 将对Fuman治疗试验进行背景。 MNK/EIF4E Ser209磷酸化在MC的纤维化激活中的作用，并测试其潜在的潜力 停止纤维化进展和外壳发展的靶标。