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Role of E-cadherin in modulating airway epithelial function and parenchymal remodeling

E-钙粘蛋白在调节气道上皮功能和实质重塑中的作用

基本信息

批准号：
10593065
负责人：
Venkataramana K Sidhaye
金额：
$ 60.29万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593065
关键词：
Adherens Junction Adhesions Affect Air Area Binding CDH1 gene Cause of Death Cell Line Cell model Cell physiology Cell-Cell Adhesion Cells ChIP-seq Characteristics Chronic Chronic Bronchitis Chronic Obstructive Pulmonary Disease Cohort Studies DNA Methylation DNA Methylation Inhibition DNA methylation profiling Data Development Disease Down-Regulation E-Cadherin Elements Environment Epigenetic Process Epithelial Cells Epithelium Exposure to Fibrosis Frequencies Functional disorder Genes Genetic Engineering Genetic Polymorphism Haplotypes Human In Vitro Inflammation Inhalation Injury Knowledge Lead Liquid substance Lung Lung diseases Maintenance Maps Measures Messenger RNA Methylation Modeling Mucociliary Clearance Mus Nuclear Pathway interactions Patients Phenotype Population Study Post-Translational Protein Processing Predisposition Proteins Pulmonary Emphysema Quantitative Trait Loci Regulation Regulatory Element Research Personnel Risk Role Secretor blood group alpha-2-fucosyltransferase Site Smoke Surface Testing Therapeutic Tissues Trachea Transcript United States Up-Regulation Variant airway epithelium airway remodeling alveolar destruction alveolar epithelium cigarette smoke cigarette smoke-induced epigenetic regulation exposure to cigarette smoke functional improvement improved knock-down methylation pattern morphometry mortality mouse model novel overexpression preservation prevent promoter protein E pulmonary function decline restoration

项目摘要

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the 4th leading cause of death in the US with emphysema progression and lung function decline with evidence of poor mucociliary clearance and airway epithelial changes as well as alveolar destruction. We have found that in COPD there is a significant decrease in adherens junction protein E-cadherin, which is a primary component dictating cell-cell adhesion a finding which has been verified by several investigators and in large cohort studied. In this proposal, we will decipher the effects of E-cadherin regulation in promoting changes in epithelial function in the airways and parenchymal modeling and determine if increased E-cadherin protects the epithelia and the lungs from cigarette smoke (CS). We propose that decreased lung epithelial E-cadherin leads to loss of polarity of the epithelial cell, disrupts the epithelial barrier f and decreases ciliary beat frequency to promote airway dysfunction. Furthermore, we propose that loss of E- cadherin promotes parenchymal remodeling. We will dissect two specific mechanisms which could contribute to decreased protein levels. In Aim 1, we will determine if E-cadherin knockdown in cells, ex vivo trachea and mouse models lead to epithelial dysfunction and altered tissue integrity indicating that loss of E-cadherin with chronic smoke exposure or in patients with COPD serves a causal role in the development of COPD. Specifically, we will determine if lung E-cadherin loss alters epithelial polarity and decreases ciliary beat frequency, mucociliary clearance, and maintenance of the air surface liquid. In addition, we will determine if E- cadherin loss promotes parenchymal remodeling and inflammation using mouse models. In Aim 2, we will study novel mechanisms by which E-cadherin is decreased in the context of CS exposure and COPD. Specifically, we will study if epigenetic regulation of the promoter contributes to decrease in mRNA and protein abundance. Our data shows that CDH1 is methylated in an area rich with regulatory elements, so we will study these elements to determine what is altered with CS exposure. In addition, we have identified a post- translational modification which correlates with E-cadherin function in population studies. Specifically, we will determine if terminal fucosylation of E-cadherin increases its adhesion strength to enhance function. We have identified a specific identified polymorphism or a haplotype that is associated with functional changes and will genetically engineer this into a lung cell line to determine if these affect E-cadherin based cell-cell adhesion and function. In addition, we will determine if mice lacking this fucosylation have increased susceptibility to CS exposure. In Aim 3, we will perform proof of concept studies to determine if upregulation of E-cadherin serves as a therapeutic strategy in primary human cells and mouse models. In addition, we will determine if manipulating the pathways identified in Aim 2 upregulate E-cadherin and improve function in the context of CS exposure.

项目总结