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.

项目摘要慢性阻塞性肺疾病（COPD）是一种慢性炎症性疾病，被认为是驱动的通过蛋白酶 - 抗蛋白酶不平衡。导致这种失衡的机制尚未完全理解。最近的工作表明，外泌体（细胞释放的小纳米植物）活化的嗜中性粒细胞（PMN）在脱粒PMN中覆盖在中性粒细胞弹性酶（NE）中，这外泌体相关的NE提供了其免受天然抗蛋白酶Alpha-1-抗抗蛋白酶（α1AT）的保护。这种对α1AT的抗性使外泌体的NE在引起COPD时具有更多的对数的潜力小鼠模型中的疾病样表型比溶液中的游离NE。这些PMN外泌体可以结合 I型胶原蛋白和结构性细胞外基质（ECM）蛋白质。具有更大的意义，这些 PMN衍生的NE+外泌体可能在小鼠模型中引起肺泡破坏，这些NE+外泌体可以在COPD患者的BALF中找到，但不健康，从不吸烟者对照，表明与外泌体NE相关的重要作用在COPD疾病进展中。该赠款将确定 NE与PMN外泌体表面的结合机制，并专注于分子破坏这种关联，使NE容易受到α1AT失活的影响。此外，这笔赠款将开发NE+ PMN外泌体产生和疾病转移到幼稚小鼠的吸烟小鼠模型，有效地创建疾病的小鼠转移模型。此外，该赠款将与 COPD患者BALF中存在PMN NE+外泌体，并具有COPD的其他重要参数严重程度。此外，PMN从其他侵入性的患者流体样本，串行中得出的NE+外泌体和痰液，将被量化，它们将疾病转移到小鼠COPD模型的能力将是与患者BALF相比。另外，可以从事分离ne的物质外泌体表面可以发展为潜在的治疗靶标。