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Mechanisms of Nanoparticle Modulation of Allergic Lung Disease

纳米粒子调节过敏性肺病的机制

基本信息

批准号：
10632116
负责人：
James Christopher Bonner
金额：
$ 49.22万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632116
关键词：
Adsorption Airway Disease Airway Fibrosis Allergens Allergic Amines Area Artificial nanoparticles Asthma Binding Biological Biological Assay Bronchial Spasm Cell Communication Cell surface Cells Chronic Data Disease Environment Exposure to Extrinsic asthma G-Protein-Coupled Receptors Genetic Predisposition to Disease Goals Health House Dust Mite Allergens Human Immune In Vitro Industry Inflammation Inhalation Inhalation Exposure Interferons Knock-out Knockout Mice Knowledge Libraries Lung Lung diseases Macrophage Mediating Metaplasia Molecular Target Mucous body substance Mus PAR-2 Receptor Pathology Phenotype Predisposition Process Property Proteins Proteomics Public Health Pulmonary Fibrosis Pulmonary Inflammation Pyroglyphidae Reporting Research Project Grants Respiratory Disease Risk Rodent Rodent Model Role STAT1 gene STAT3 gene STAT6 gene Serine Protease Signal Transduction Surface Testing Therapeutic Wild Type Mouse Work airway hyperresponsiveness allergic airway disease cell type chemical addition chemical group chronic respiratory disease consumer product cytokine design double walled carbon nanotube eosinophilic inflammation hazard inhibitor nanoparticle novel profibrotic cytokine public health relevance response transcription factor

项目摘要

Project Summary Multi-walled carbon nanotubes (MWCNTs) are engineered nanoparticles with numerous applications and they are commonly ‘functionalized’ by the addition of chemical groups (e.g., carboxyl or amine groups) to modify their unique physicochemical properties. Increasing evidence in rodent models indicate that MWCNTs are an emerging risk for lung diseases. In particular, MWCNTs exacerbate allergen-induced airway disease in rodents, suggesting a potential hazard for humans with allergic asthma. The long-term pathology of asthma features airway fibrosis and mucous cell metaplasia, defined herein as allergic airway disease. Importantly, current asthma therapies treat inflammation and bronchospasm, but do not reduce allergic airway disease. Therefore, elucidating the mechanism(s) through which nanoparticles exacerbate allergic airway disease would fill critical knowledge and treatment gaps. We propose a mechanism of nanoparticle exacerbation of chronic airway disease mediated by the adsorption of proteolytic house dust mite (HDM) allergens to the surface of MWCNTs to form an ‘allergen corona’. Allergens in the corona have increased proteolytic activity and activate the protease-activated receptor-2 (PAR2) on lung macrophages. Triggering of PARs has been implicated in M2-like ‘pro- fibrotic’ polarization of macrophages, a process that is regulated by STAT transcription factors. Our preliminary data show that PAR2 deficiency in cells or mice increases STAT1 signaling but decreases STAT3 signaling. Therefore, we hypothesize that MWCNTs exacerbate allergic airway disease by enhancing the proteolytic activity of allergens to increase PAR2 activation in macrophages leading to induction of STAT3 signaling and suppression of STAT1 signaling. In Aim 1 we will characterize the allergen corona on MWCNTs exposed to HDM extract, determine that functionalization alters corona formation, and show that corona allergens have enhanced proteolytic activity. In Aim 2 we will determine whether MWCNTs with HDM allergen corona activate PAR2 in macrophages in vitro to induce STAT3 signaling or suppress STAT1 signaling to enhance pro-fibrotic cytokine expression. In Aim 3 we will determine whether MWCNTs with HDM allergen corona exacerbate allergic airway disease in mice and whether this is dependent on PAR2 induction of STAT3 activation or suppression of STAT1 activation. Completion of these studies will define a novel mechanism and fundamental basis through which nanoparticles exacerbate allergic airway disease. This work will have significant and broad implications for a variety of engineered nanoparticles and their impact on human health.

项目总结