Pathogenic Exosomes in COPD

COPD 中的致病性外泌体

• 批准号: 10571796
• 负责人: J Edwin Blalock
• 金额: $ 102.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2030-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571796
• 关键词: African American; Animal Model; Animals; Asian; Biochemistry; Cardiology; Caucasians; Cell Death; Cells; Cellular biology; Chemistry; Chronic; Chronic Obstructive Pulmonary Disease; Disease; Extracellular Matrix; Extracellular Matrix Degradation; Faculty; Goals; Grant; Human; Human Biology; Immune; Inflammation; Latina; Leukocyte Elastase; Lung; Medical Students; Mentors; Mission; Modeling; Molecular Biology; Mus; National Heart, Lung, and Blood Institute; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Phase; Phenotype; Physicians; Physiology; Postdoctoral Fellow; Protease Inhibitor; Protein Kinase Interaction; RIPK1 gene; Research; Resistance; Resources; Role; Scientist; Smoker; Smoking; Strategic vision; Surface; Tissues; Training; Translating; United States National Institutes of Health; Work; alpha 1-Antitrypsin; chronic inflammatory disease; cigarette smoke-induced; disease phenotype; doctoral student; exosome; exposure to cigarette smoke; extracellular; extracellular vesicles; human disease; innovation; member; mouse model; multidisciplinary; neutrophil; new therapeutic target; novel; novel diagnostics; novel therapeutics; pathogen; programs; therapeutic development

PROJECT SUMMARY The thesis of this R35 Program is that immune cell derived “pathogenic exosomes” are key players in chronic obstructive pulmonary disease (COPD) and that their role can be modeled in a smoking mouse model of exosome transfer to attain novel understanding of the disease which can in turn be applied to COPD. This R35 Program is at the cutting edge of innovation having discovered the existence of alpha-1 antitrypsin (α-1AT) resistant neutrophil elastase (NE)+ neutrophil (PMN)-derived exosomes in COPD patients. In doing so, the Program has challenged the concept that protease activity is solely solution phase and shown extracellular matrix (ECM) proteolytic activity is hugely enhanced by protease attachment to the extracellular vesicle (EV) surface. Consequently, we: i) describe what appears to be the first EV that can transfer a COPD-like phenotype from humans to mice; ii) elucidate a new mechanism by which proteases escape anti-protease inactivation, leading to ECM degradation and cell death via receptor-interacting protein kinase 3 (RIPK3); iii) describe a new model that transfers a COPD phenotype from cigarette smoke (CS) exposed mice to naïve mice via immune cell- derived exosomes; iv) use the mouse model to discover a new CS induced protective mechanism against exosomal damage as well as a mechanism for exosomal self-propagation; v) uncover new therapeutic targets for exosomal damage and; vi) translate the new findings to better understand disease in COPD patients and smokers. Another highly significant aspect of this research Program is training/mentoring. In the past ten years, which includes the PI's inaugural R35 grant, the PI has been or is currently mentor to two PhD students, five medical students, an MD/PhD student, six K awardees, four postdoctoral trainees, a pulmonary fellow, and a cardiology fellow. The PI currently mentors seven junior faculty members. Overall, our Program is both multidisciplinary – employing chemistry, biochemistry, molecular and cell biology, animal physiology, etc. – and translational in pairing basic scientists with physician scientists. Our team and trainees fulfill the NHLBI/NIH mission to have diversity by including African American, Latina, Asian, and Caucasian members. Our program fulfills all four goals of the NHLBI Strategic Vision by: a) elucidating a new exosomal aspect of human biology; b) reducing human disease by new therapeutic development against the exosomal pathway; c) developing a work force and an animal model exosome resource and; d) translating the exosome research to human disease.

项目摘要 该R35程序的论点是Imune细胞得出的“致病外泌体”是 慢性阻塞性肺疾病（COPD）的关键参与者及其作用可能是 以外泌体转移的吸烟小鼠模型建模，以获得对 疾病又可以应用于COPD。 创新发现存在α-1抗胰蛋白酶（α-1AT）抗性中性粒细胞 弹性酶（NE）+中性粒细胞（PMN）衍生的COPD患者的外泌体。 挑战了蛋白酶活动是唯一溶液相位溶液阶段的概念 细胞外基质（ECM）蛋白质活性通过蛋白酶的附着而大大增强 细胞外囊泡（EV）表面。 可以将类似COPD的表型从人类转移到小鼠； 蛋白酶逃脱抗蛋白酶灭活，导致ECM降解和细胞 通过受体相互作用的蛋白激酶3（RIPK3）死亡； 通过免疫细胞暴露于香烟烟雾（CS）暴露于幼稚小鼠的COPD表型 派生的外泌体； 反对外泌体损伤的机制以及外泌体自我传播的机制； v）发现外泌体损害的新治疗靶 更好地了解COPD患者和吸烟者的疾病。 该研究计划的另一个重要方面是培训/指导 过去的十年，包括PI的首届R35赠款，PI已或目前是 两名博士生，五名医学生，一名医学博士学位学生，六个K奖，四个 博士后学员，肺部研究员和心脏病研究员。 总体而言，七个初级教师。 化学，生物化学，分子和细胞生物学，动物生理学等 将基本科学家与医师科学家配对。 通过在内 我们的计划实现了NHLBI战略愿景的所有四个目标 人类生物学的新外泌体方面 反对外泌体途径； c）发展劳动力和动物模型 外部资源； d）将外泌体研究转化为人类疾病。