Autotaxin Lysophophatidic acid pathway in bronchiolitis obliterans post-lung tran

肺移植后闭塞性细支气管炎中自分泌运动因子溶血磷脂酸途径

基本信息

批准号：
8694759
负责人：
Vibha N Lama
金额：
$ 51.88万
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：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694759
关键词：
AXIN2 protein Acids Affect Allografting Animals Binding Biological Assay Biological Markers Bronchiolitis Obliterans Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cell Differentiation process Cell Nucleus Cells Cessation of life Chronic Cicatrix Clinical Trials Collagen Cyclin D1 Data Deltastab Dependency Development Disease Drug Targeting Embryo Family Felis catus Fibrosis Future Gene Targeting Generations Genetic Transcription Glycogen Synthase Kinase 3 Histology Human Human Activities Hydroxyproline Immunosuppression Investigation Label Lead Ligation Link Lipids Lung Lung Transplantation Lymphoid Lysophosphatidylcholines Lysophospholipase Lysophospholipids Mediating Membrane Lipids Mesenchymal Mesenchyme Modeling Mus Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Phenotype Phospholipase C Phosphorylation Play Population Protein Kinase C Publishing Receiver Operator Characteristics Reporter Respiratory physiology Role Route Sampling Scheme Secondary to Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Solid Syndrome TCF Transcription Factor Testing Therapeutic Time Tissues Tomatoes Transcriptional Activation Transgenic Mice Transplant Recipients Transplantation Up-Regulation Work activating transcription factor autocrine cohort enhancer binding protein extracellular fibrogenesis graft failure human data in vivo lung allograft lysophosphatidic acid migration mortality novel novel therapeutic intervention nuclear factors of activated T-cells preclinical study prevent prognostic protein expression public health relevance research study therapeutic target transcription factor vzg-1 Receptor

项目摘要

DESCRIPTION (provided by applicant): Impaired lung function secondary to fibrotic scarring and obliteration of small airways, termed bronchiolitis obliterans syndrome (BOS), is the major cause of chronic graft failure and mortality following lung transplantation. Understanding mechanistic pathways involved in lung allograft fibrogenesis is the key to novel therapeutic approaches in this arena. Studies of mesenchymal cells (MCs) from human lung allografts have led us to target a novel signaling pathway of MC mobilization and activation. An increase in number of donor-derived MCs is seen in the bronchoalveolar lavage (BAL) of patients with BOS. MCs from BOS lungs also demonstrated a stable activated phenotype marked by an increased collagen and ¿-catenin protein expression as well as an increased autotaxin (ATX) secretory activity. ATX is a secreted lysophopholipase D which generates lysophosphatidic acid (LPA), a bioactive lipid with a role in tissue fibrosis, from membrane lipids. Our published work has revealed a unique signaling cascade where through LPA1 ligation and subsequent phosphokinase-C mediated glycogen synthase kinase-3¿ activation, LPA leads to ¿-catenin stabilization and transcriptional activation. New preliminary data demonstrates that autocrine ATX secretion and LPA1 ligation contributes to stable ¿-catenin and collagen upregulation noted in MCs isolated from human fibrotic lung grafts. Furthermore, LPA levels were noted to be higher in BAL samples from patients with BOS. This human data has led us to propose experiments investigating the in vivo role of ATX-LPA-¿-catenin pathway in pathogenesis of BO and to investigate if LPA1 antagonism can be a potential therapeutic option in this disease. To achieve these aims we have established a whole lung mouse orthotopic lung transplant model where a moderate MHC mismatch leads to development of airway fibrosis by day 28. In Aim 1, we propose to investigate the time course of ATX and LPA upregulation in the resident MCs and other cellular components of the allograft in vivo using this murine model. We will utilize mice with BAC florescent labeling of Foxf1, a transcription factor seen in embryonic lung mesenchyme and shown to be highly expressed in lung MCs, to specifically identify and study graft-resident MCs. These studies will also inform us of the role of graft-resident MCs in fibrogenesis. Aim 2 will focus on understanding the role of ¿-catenin in MC differentiation and dissecting the mechanisms by which it affects the cells fibrotic functions. The mechanistic pathways will be studied in human cells. However, we will utilize a reporter mouse (Axin2LacZ) to follow ¿-catenin transcriptional activity during allograft fibrogenesis and test the in vivo rol of LPA1 ligation in MC ¿-catenin activation. In Aim 3 we will determine if LPA levels in BAL samples can predict subsequent development of BOS. Importantly, we will test if LPA1 antagonist can prevent onset or progression of allograft fibrosis in the murine orthotopic single lung transplant model. The proposed work will be the first investigation of ATX/LPA/LPA1/ ¿-catenin signaling in BOS and will provide important rationale for future clinical trials targeting this pathway in lung transplantation.

描述（申请人证明）：肺部造成的肺部功能受损，而小气道ERANS综合征（BOS）是慢性移植和死亡率的主要原因人类肺同种异体的间充质细胞（MC）导致了MC动员和激活的靶向途径。 - 养生蛋白以及自身Xtx蛋白（ATX）的增加是一种分泌的溶血酶D，产生溶血酸（LPA），这是一种生物活性脂质，在我们的出版工作中，在组织纤维化中起作用。那里的LPA1连接以及随后的磷酸激酶-C介导的糖原合成激酶-3¿3¿3¿激活，LPA导致� - 神宁宁氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸磷酸化。 - 在人类纤维化的肺移植物中分离出的MC中的蛋白质和收集。 -cateninininininininininininininininininininininininininininininated We Have Established a Whole Lung Mouse ORTHOTOPIC LUNG TRANSPLANT MODEL WHERE A MODERATE MHC MISMATCH LEADS to Development of Airway Fibros by Airway Fibros by. Day 28. IN AIM 1, We Propose to Investigate The Time Course of LPA Upregulation in The Resident Mcs使用该鼠模型的其他组件。居住在火生成中的居民MC的作用。 - 在MC中的蛋白质和它影响细胞的机制。 - 在同种异体移植纤维发生过程中 - 蛋白蛋白转录活性，并测试Mc�C中的LPA1结扎的体内ROL -Catenininne 3我们将确定BAL样品中的IFA水平可以预测BOS的后期。 - BOS和Will Will Will Will Will Will in then Cliale Clials的靶向试验试验的未来Cliale Clials的重要基本原理为肺移植中的这种途径提供了重要的基本原理。