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Mechanisms of Airway Epithelial Barrier Dysfunction by Respiratory Syncytial Virus and Environmental Stimuli

呼吸道合胞病毒和环境刺激导致气道上皮屏障功能障碍的机制

基本信息

批准号：
10657436
负责人：
Fariba Rezaee
金额：
$ 43.99万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657436
关键词：
3-Dimensional Actin-Binding Protein Actins Acute Adult Adverse effects Affect Age Air Pollution Airway Disease Antioxidants Apical Artificial nanoparticles Attenuated Cell Separation Child Childhood Complex Cyclic AMP Cytoskeleton Data Deposition Distal Down-Regulation EMS1 gene Environmental Pollutants Environmental Pollution Epidemiology Epithelial Cells Epithelium Event Exposure to Filament Free Radicals Functional disorder Generations Hospitalization Host Defense Household Human Human Cell Line In Vitro Infant Inflammation Injury Knockout Mice Link Lower Respiratory Tract Infection Lung Measurement Mediating Methods Microfilaments Mission Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Nanotechnology Organoids Outcome Oxidative Stress Oxidative Stress Induction Particle Size Particulate Matter Pathology Pathway interactions Personal Satisfaction Polymers Production Reporting Research Respiration Disorders Respiratory Syncytial Virus Infections Respiratory syncytial virus Risk Rodent Role Severities Signaling Molecule Source Standardization Stimulus Structure Testing Therapeutic Intervention United States National Institutes of Health Vascular Endothelium Vascular Permeabilities Virus Virus Diseases Virus Replication airway epithelium airway hyperresponsiveness bronchial epithelium clinically relevant commercial application consumer product depolymerization design epithelial injury gain of function high risk in vivo in vivo Model injured airway innovation insight intestinal epithelium loss of function mortality mouse model nanomaterials nanoparticle new therapeutic target novel particle polymerization titanium dioxide young adult

项目摘要

ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (ALRI) in children and high-risk adults worldwide. Our data demonstrate that RSV infection results in a ‘leaky airway’ by disrupting epithelial apical junctional complexes (AJC), which regulate the airway epithelial barrier. We show that RSV- mediated disruption of AJC is accompanied by disassembly of the perijunctional actin cytoskeleton, and downregulation of cortactin - a key actin-binding protein. Cortactin deficiency has been previously implicated in destabilizing the vascular endothelial and intestinal epithelial barrier. However the causal link between RSV- induced leaky barrier, actin cytoskeletal rearrangements and cortactin deficiency have not been established. In addition, epidemiological reports suggest a strong association between exposure to ambient particulate matter (PM) and increased risk of ALRI. Nanoparticles (NPs) are extremely small PM, with the greater ability to become deposited in distal airways and evade host defenses compared to smaller particles. Our preliminary data demonstrate that pre-exposure of bronchial epithelial cells to NP not only enhances RSV-induced AJC disassembly and actin cytoskeleton disruption, but augments viral infection. Based on our novel observations, we formulated the central hypotheses that a) RSV induces disruption of the airway epithelial barrier by triggering depolymerization of the perijunctional actin cytoskeleton, and by downregulating cortactin; and b) that disruption of the epithelial barrier by nanoparticles worsens RSV-induced airway epithelium injury. We will test our hypotheses through the following Specific Aims: Aim 1: To determine the role of cortactin-dependent actin filament dynamics in RSV-induced airway epithelial barrier dysfunction. Using human bronchial epithelial cells isolated from pediatric donors, and a mouse model of cortactin null mice, we will investigate (i) RSV effect on actin cytoskeletal dynamics, (ii) the functional role of cortactin on actin dynamics and AJC structure, and (iii) the functional roles of Rap-1. We will also use a 3-D human lung organoids model detailing the effects of AJC disruption upon RSV infection, which offers an innovative platform to study complex host-environmental interactions. Aim 2: To determine if nanoparticles enhance RSV-induced disruption of the airway epithelial barrier. Using in vitro and in vivo models, we will (i) characterize the effects of particle size on barrier integrity, (ii) study role of oxidative stress on AJC function, and (iii) define the effects of exposure to NP on AJC dysfunction. The proposed research is significant and relevant to the NIH’s mission as we aim to explore the clinically relevant consequences of RSV infection on airway barrier integrity, and how exposure to environmental pollutants worsens RSV infection. Our approach is innovative because it will provide new mechanistic insight in to the roles of RSV in AJC disassembly, as well as novel insight in to the effects of NPs in enhancing RSV- induced AJC disruption. The identified pathways will provide new targets for therapeutic intervention and the potential for positively impacting the management of RSV disease.

摘要