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: 10864502
• 负责人: Vibha N Lama
• 金额: $ 57.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-08 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10864502
• 关键词: Airway Fibrosis; Allografting; Autocrine Communication; Automobile Driving; Bronchiolitis Obliterans; Cause of Death; Cell Separation; 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; 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; Phenotype; Phosphorylation; Phosphotransferases; Play; Procedures; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Publishing; Resistance; Role; Scheme; Serine; Signal Pathway; Signal Transduction; Solid; Syndrome; Testing; Therapeutic; Therapeutic Trials; Transcriptional Activation; Transgenic Mice; Translational Activation; Translational Regulation; Translations; Transplant Recipients; Transplantation; Work; autocrine; beta catenin; cytokine; efficacy evaluation; fibrogenesis; graft failure; improved; in vitro activity; in vivo; inflammatory milieu; inhibitor; kinase inhibitor; lung allograft; metaplastic cell transformation; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; 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.

项目总结/摘要 慢性肺移植物功能障碍（CLAD）的特点是进行性移植失败的发展，在50%的肺移植 接受者5年，是这种挽救生命的手术后长期结果不佳的主要原因。 主要的临床表现是发展为持续性阻塞性毛细血管缺陷，称为细支气管炎 闭塞性综合征（BOS）是由小气道的纤维化闭塞或闭塞性细支气管炎（BO）引起的。 移植物驻留间充质细胞（mesenchymal cells，MCs）在BO的发病机制中起着关键作用， 表明MCs的自主激活以基质沉积增加和MCs的稳定激活为标志， 促纤维化途径是同种异体移植物纤维化和功能障碍的关键驱动因素。各种信号传导途径， 显示在真核翻译起始因子4 E（eIF 4 E）水平上会聚，以调节关键的纤维化 在BOS MC中的功能类似于胶原I表达。在本申请中，我们的目标是研究MAP激酶的作用- 相互作用的丝氨酸/苏氨酸激酶（MNK）诱导eIF 4 E在丝氨酸209处的直接磷酸化， BOS MCs的纤维化转化，并确定MNK/eIF 4 E途径对发病机制的贡献 移植后的BO已经证明MNK激酶诱导eIF 4 E在丝氨酸209处的磷酸化 在促进其致癌潜力方面至关重要，但尚未在纤维化的背景下进行研究。我们 初步数据表明，在来自患者的MC中，eIF 4 E在丝氨酸209处的磷酸化组成性更高， 关于BOS发现eIF 4 E磷酸-S209在调节关键的纤维化蛋白autotaxin中至关重要， 维持BOS MC的纤维化功能。MNK信号在BOS细胞中上调，遗传或 MNK活性的药理学靶向抑制EIF 4 E磷酸化S209和BOS MC的纤维化功能， 体外发现用MNK抑制剂eFT-508的体内治疗减少原位小鼠中的同种异体移植物纤维化。 肺移植模型在目标1中，我们将利用来源于患者± BOS的MC来解剖分子结构。 eIF 4 E Ser 209磷酸化促进人肺纤维化转化的机制 MC目的2将在小鼠原位肺中研究MNK/eIF 4 E信号传导在BO发生中的作用 利用MNK 1/2 Knockout和eIF 4 ES 209 A/A突变小鼠靶向MNK/eIF 4 ES 209建立BO移植模型 捐赠者的肺里新型口服MNK 1/2抑制剂eFT 508在小鼠原位全细胞中的临床前研究 肺移植BO模型，评估目的3中提出的纤维化和免疫/炎症终点 将为未来的人体治疗试验奠定基础。这些研究将共同揭示新的光 MNK/eIF 4 E Ser 209磷酸化在MC纤维化活化中的作用，并测试其作为有吸引力的 目的是阻止纤维化进展和CLAD的发展。

项目成果

Lysophosphatidic acid induces migration of human lung-resident mesenchymal stem cells through the β-catenin pathway.

• DOI: 10.1002/stem.1171
• 发表时间: 2012-09
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Badri, Linda;Lama, Vibha N.
• 通讯作者: Lama, Vibha N.

Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction.

• DOI: 10.3390/cells11040699
• 发表时间: 2022-02-16
• 期刊: Cells
• 影响因子: 6
• 作者: Ram S;Verleden SE;Bell AJ;Hoff BA;Labaki WW;Murray S;Vanaudenaerde BM;Vos R;Verleden GM;Kazerooni EA;Galbán S;Hatt CR;Han MK;Lama VN;Galbán CJ
• 通讯作者: Galbán CJ

Ecto-5'-nucleotidase (CD73) attenuates allograft airway rejection through adenosine 2A receptor stimulation.

• DOI: 10.4049/jimmunol.0901847
• 发表时间: 2010-07-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ohtsuka T;Changelian PS;Bouïs D;Noon K;Harada H;Lama VN;Pinsky DJ
• 通讯作者: Pinsky DJ

Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis.

• DOI: 10.1038/s41598-020-77601-1
• 发表时间: 2020-12-04
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cao P;Walker NM;Braeuer RR;Mazzoni-Putman S;Aoki Y;Misumi K;Wheeler DS;Vittal R;Lama VN
• 通讯作者: Lama VN

Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts.

• DOI: 10.1016/j.ajpath.2011.01.058
• 发表时间: 2011-06
• 期刊: The American journal of pathology
• 作者: N. Walker;Linda N Badri;S. Wettlaufer;A. Flint;U. Sajjan;P. Krebsbach;V. Keshamouni;M. Peters-Golden;V. Lama