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A Pathogenic Smoke Associated Neutrophilic Exosomal Pathway.

致病性烟雾相关的中性粒细胞外泌体途径。

基本信息

批准号：
10416774
负责人：
Kristopher R. Genschmer
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10416774
关键词：
Alveolar Antibodies Binding Biological Markers Biology Cells Characteristics Chronic Obstructive Pulmonary Disease Collagen Type I Complex Coughing Development Disease Disease Progression Disease model Dissociation Early identification Excision Extracellular Matrix Extracellular Matrix Proteins Future Generations Goals Grant Human In Vitro Individual Inflammation Inflammatory Integrins Leukocyte Elastase Link Liquid substance Lung Lysine Macrophage-1 Antigen Measures Membrane Methods Modeling Molecular Mus Paper Pathogenesis Pathogenicity Pathway interactions Patients Peptide Hydrolases Phase Phenotype Population Production Protamines Protease Inhibitor Proteoglycan Pulmonary Emphysema RIPK3 gene Resistance Respiratory Failure Risk Factors Role Sampling Serine Protease Serum Severity of illness Shortness of Breath Site Smoke Smoker Smoking Sputum Surface Therapeutic Work airway obstruction alpha 1-Antitrypsin alveolar destruction chronic inflammatory disease cohort disease phenotype exosome exposure to cigarette smoke high risk improved in vivo inhibitor mouse model nanovesicle neutrophil never smoker non-smoking pancreatic elastase II patient stratification risk stratification smoking-related lung disease therapeutic target

项目摘要

Project Summary Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease believed to be driven by protease-antiprotease imbalance. The mechanisms leading to this imbalance have yet to be fully understood. Recent work has suggested that exosomes (small nanovesicles released by cells) from activated neutrophils (PMNs) are coated in neutrophil elastase (NE) from degranulated PMNs and this exosome associated NE renders it protected from its native antiprotease, alpha-1-antitrypsin (α1AT). This resistance to α1AT makes exosome associated NE several log-fold more potent in causing a COPD disease-like phenotype in mouse models than free NE in solution. These PMN exosomes can bind to type I collagen and degrade structural extracellular matrix (ECM) proteins. Of bigger significance, these PMN derived NE+ exosomes can cause alveolar destruction in a mouse model and these NE+ exosomes can be found in the BALF of COPD patients, but not healthy never smoker controls, indicating an important role for exosome associated NE in COPD disease progression. This grant will identify the mechanism of NE association to the surface of PMN exosomes as well as focusing on molecules to disrupt this association, rendering the NE susceptible to α1AT inactivation. Furthermore, this grant will develop a smoking mouse model of NE+ PMN exosome production and disease transfer to naïve mice, effectively creating a mouse-mouse transfer model of disease. Additionally, this grant will correlate the presence of PMN NE+ exosomes in COPD patient BALF with other significant parameters of COPD severity. Moreover, PMN derived NE+ exosomes from other, less invasive patient fluid samples, serum and sputum, will be quantified and their ability to transfer disease to mouse model of COPD will be compared to those from patient BALF. Additionally, substances studied that can dissociate NE from the exosome surface can be developed into potential therapeutic targets.

项目总结