Activated Neutrophilic Exosome as Biomarker and Therapeutic Target in COPD

活化的中性粒细胞外泌体作为慢性阻塞性肺病的生物标志物和治疗靶点

• 批准号: 10404995
• 负责人: Derek Russell
• 金额: $ 16.49万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404995
• 关键词: Address; Alveolar; Animal Model; Attenuated; Automobile Driving; Binding; Biological; Biological Markers; Bronchoalveolar Lavage Fluid; Cause of Death; Cells; Characteristics; Charge; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Collagen Type I; Data; Development; Disease; Disease Progression; Environment; Equilibrium; Extracellular Matrix; Flow Cytometry; Foundations; Functional disorder; Genetic; Goals; Human; In Vitro; Inflammation; Inherited; Integrins; Interruption; Knockout Mice; Leukocyte Elastase; Link; Lung; Macrophage-1 Antigen; Measures; Mediating; Medical; Modeling; Monitor; Mus; Obstruction; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Phase; Phenotype; Process; Prognosis; Property; Protamine Sulfate; Protease Inhibitor; Proteoglycan; Proteolysis; Pulmonary Emphysema; Research Project Grants; Resistance; Risk; Risk Factors; Sampling; Serum; Smoker; Smoking; Source; Specimen; Sputum; Structural Protein; Surface; Symptoms; Techniques; Therapeutic; Tissues; Training; Translating; alpha 1-Antitrypsin Deficiency; alveolar destruction; biomarker performance; career development; chronic inflammatory disease; cohort; design; disease phenotype; disorder risk; exosome; experience; former smoker; human disease; in vivo; innovation; molecular array; mouse model; nanovesicle; neutrophil; never smoker; novel; respiratory; therapeutic target; treatment response

Project Summary/Abstract: Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the world, is a chronic inflammatory disease thought to be driven at least in part by derangements of protease-antiprotease balance. Recent discoveries have suggested that proteases such as neutrophil elastase (NE) can be associated with exosomes released by neutrophils (PMNs). Exosomes are nanovesicles released by the cell into the environment. NE is enzymatically active when associated with exosomes yet it is markedly resistant to inhibition by α-1 antitrypsin (α-1AT) in this form. Exosomal NE is several log-fold more potent in causing COPD in mouse models than soluble NE, and the exosomes themselves are able to traverse tissue planes and bind to structural proteins in the lung such as type I collagen, focusing the proteolysis upon its substrate. Importantly, exosomes derived from PMNs that are capable of causing NE-dependent alveolar destruction in mice have been found in bronchoalveolar lavage fluid (BALF) of subjects with COPD, but not healthy controls. Because of these findings, it seems likely that this exosome-associated form of NE may be more important to extracellular matrix destruction (and thus COPD pathogenesis) than conventionally measured soluble NE. This research project will quantify the PMN-derived, NE+ exosome burden within three well-phenotyped cohorts of subjects with COPD as well as non-obstructed never smoker and current/former smoker control subjects. Furthermore, the PMN-derived, NE+ exosome profile of sputum and serum will be assessed to define the biomarker utility of this process using less invasively derived specimens than BALF. These findings will be correlated with various clinically validated measures of COPD disease progression, symptom burden as well as disease sub-phenotype and will be correlated with development of COPD among subjects at risk for this disease. Moreover, this project will develop and optimize an animal model of pathogenic exosome transfer, delineate the mechanism of NE binding to the PMN exosome surface, and advance rational strategies designed to interrupt exosome pathogenicity. These studies will form the foundation for the use and further study of PMN-derived, NE+ exosomes as biomarkers of disease activity and potential therapeutic targets.

项目概要/摘要： 慢性阻塞性肺疾病（COPD）是世界上第四大死亡原因， 是一种慢性炎症性疾病，被认为至少部分是由 蛋白酶-抗蛋白酶平衡紊乱。最近的发现表明 蛋白酶如中性粒细胞弹性蛋白酶（NE）可以与外泌体结合， 由中性粒细胞（PMNs）释放。外泌体是由细胞释放到细胞内的纳米囊泡。 环境保护NE在与外来体结合时具有酶活性，但它在与外来体结合时具有酶活性。 对这种形式的α-1抗胰蛋白酶（α-1AT）的抑制有显著抵抗力。外泌体NE是 在小鼠模型中引起COPD的效力是可溶性NE的几倍， 外泌体本身能够穿过组织平面并结合到结构上， 肺中的蛋白质，如I型胶原蛋白，将蛋白质水解集中在其底物上。 重要的是，来源于能够引起NE依赖性炎症的PMN的外泌体， 在小鼠的支气管肺泡灌洗液（BALF）中发现了肺泡破坏， COPD受试者，但不是健康对照。由于这些发现， 这种外泌体相关形式的NE可能对细胞外基质更重要， 与常规测量的可溶性NE相比，这是一种更好的破坏（因此是COPD发病机制）。 该研究项目将在三个月内量化PMN衍生的NE+外泌体负担。 表型良好的COPD受试者队列以及非阻塞性Never 吸烟者和当前/既往吸烟者对照受试者。此外，PMN衍生的， 将评估痰液和血清的NE+外泌体特征以定义生物标志物 使用比BALF更少侵入性来源的标本的该过程的实用性。这些 结果将与COPD疾病的各种临床验证措施相关 进展、症状负担以及疾病亚表型，并将与 在有COPD风险的受试者中发生COPD。而且这 该项目将开发和优化致病性外泌体转移的动物模型， 阐明NE与PMN外泌体表面结合的机制， 旨在中断外来体致病性的合理策略。这些研究将形成 为使用和进一步研究PMN衍生的NE+外泌体作为 疾病活动的生物标志物和潜在的治疗靶点。