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Chronic Lung Allograft Dysfunction: Role for Tumor Suppressor LKB1 in Exosomes

慢性肺同种异体移植功能障碍：肿瘤抑制因子 LKB1 在外泌体中的作用

基本信息

批准号：
10516866
负责人：
THALACHALLOUR MOHANAKUMAR
金额：
$ 40.7万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516866
关键词：
5&apos -AMP-activated protein kinase Acute Aldehydes Allografting Automobile Driving Binding Biological Markers Biological Models Biopsy Bronchiolitis Obliterans CD80 gene CD86 gene CDC37 gene Cell Culture Techniques Cell Line Cells Chronic Clinical Cyclic AMP-Dependent Protein Kinases Data Development Diagnosis Down-Regulation Early identification Epithelial Epithelial Cells Family Fibrosis Flow Cytometry Functional disorder Genetic Transcription Goals Heat-Shock Proteins 90 Human Immunologics In Vitro Institutes Intervention Liver Lung Lung Transplantation Lung diseases MHC Class II Genes Mediating Mesenchymal Metabolism Methods Modeling Molecular Morphology Pathogenesis Pathology Pathway interactions Patients Phosphorylation Phosphotransferases Plasma Platelet-Derived Growth Factor Receptor Play Property Prostaglandin D2 Protein Kinase Receptor Signaling Regulation Reporting Risk Risk Factors Role STK11 gene Sampling Signal Pathway Signal Transduction Syndrome TNFRSF5 gene Testing Therapeutic Transforming Growth Factor beta Transplant Recipients Transplantation Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation Viral Respiratory Tract Infection Western Blotting airway epithelium base cell growth clinical diagnosis donor-specific antibody epithelial to mesenchymal transition exosome graft dysfunction high risk in vitro Model knock-down liver function lung allograft multicatalytic endopeptidase complex nano-string novel prevent primary endpoint receptor expression receptor upregulation secondary endpoint statistics therapeutically effective transcription factor

项目摘要

Project Summary/Abstract Lung transplantation (LTx) is a therapeutic option for patients with advanced lung diseases. Long‐term survival after LTx is, however, limited by chronic lung allograft dysfunction (CLAD). CLAD most commonly manifests itself as bronchiolitis obliterans syndrome (BOS) and about 50% of recipients (LTxRs) will develop BOS within 5 years post-LTx. Epithelial-mesenchymal-transition (EMT) and fibrosis have been implicated in the pathogenesis of BOS. We demonstrated that liver kinase 1 (LKB1), a tumor suppressor gene, is downregulated in BOS but not in stable biopsies using both western blotting and aldehyde bead conjugated exosomes by flow cytometry. We also demonstrated that LKB1 knockdown induces exosome release from airway epithelial cell line, BEAS-2B, and another human airway epithelial cell line, HPBEC. Exosomes released from LTxRs with BOS also induces EMT which was regulated by LKB1 in BEAS-2B and HPBEC. NanoString analyses identified LKB1 knockdown induced PDGFRβ expression in human airway epithelial cells. We also demonstrated that biopsies from BOS LTxRs had reduced LKB1 and increased PDGFβR with inverse correlation. These novel findings indicate an important role for the tumor suppressor gene LKB1 in the regulation of PDGFβR and, therefore, fibrosis development. Studies proposed using both clinical samples and in vitro cell culture model, we will define the mechanism by which exosomes with downregulated LKB1 released from transplanted lungs mediate EMT leading to CLAD. Aim 1 of the proposal is to determine serially whether inactivation of LKB1 in exosomes isolated from plasma from LTxRs with known risk factors (primary graft dysfunction [PGD]), acute rejection [AR] and respiratory viral infections [RVI]) can be useful as a non- invasive biomarker for LTxRs at risk for CLAD. Our hypothesis is that persistent downregulation of LKB1 in exosomes will be a biomarker for LTxRs at risk for developing CLAD. The second goal is to determine and quantitate exosomes with LKB1/AMPK1 using serial retrospectively stored plasma from LTxRs with known clinical diagnosis will be a more sensitive marker for CLAD and to determine its potential to differentiate restrictive allograft syndrome and BOS by defining their immunological and molecular properties. Our third goal is to define the mechanisms by which loss of LKB1 results in EMT and upregulation of PDGFRβ and promotes the pathogenesis of CLAD. Towards this; a) we will define the regulatory mechanisms suppressing LKB1 in LTxRs with PGD, AR and RVI, risk factors for CLAD, and b) we will determine the mechanisms by which LKB1 downregulation leads to upregulation of PDGFRβ and its signaling pathways which contributes towards development of fibrosis. Results from these studies will provide novel information for the role of LKB1, in EMT and fibrosis related pathologies including CLAD following LTx.

项目总结/文摘