Pathogenic Exosomes in COPD

项目总结 这个R35计划的论点是免疫细胞衍生的致病外切体是 慢性阻塞性肺疾病(COPD)的关键参与者，他们的作用可以是 在吸烟的小鼠模型中建立外切体转移模型，以获得对 这种疾病可以反过来应用于慢性阻塞性肺病。此R35计划处于 创新发现存在抵抗α-1抗胰蛋白酶(α-1AT)的中性粒细胞 慢性阻塞性肺疾病患者弹性蛋白酶(NE)+中性粒细胞(PMN)来源的外切体。在这样做的过程中，计划 挑战了蛋白酶活性仅是溶液相的概念，并显示出 细胞外基质(ECM)的蛋白分解活性通过与 细胞外小泡(EV)表面。因此，我们：i)描述似乎是第一辆电动汽车的是什么 可以将COPD样表型从人转移到小鼠身上；ii)阐明了一种新的机制 通过这种方式，蛋白酶可以逃脱抗蛋白酶的失活，导致细胞外基质降解和细胞 通过受体相互作用蛋白激酶3(RIPK3)致死；iii)描述了一种新的模型 香烟烟雾(CS)暴露于幼稚小鼠的COPD表型通过免疫细胞- 衍生外切体；iv)利用小鼠模型发现一种新的CS诱导的保护性 防止外体损伤的机制以及外体自我繁殖的机制； 五)发现新的外体损伤治疗靶点；六)将新发现转化为 更好地了解COPD患者和吸烟者的疾病。 这项研究计划的另一个非常重要的方面是培训/指导。在 过去十年，包括PI的第一笔35卢比的赠款，PI已经或目前正在 两名博士生、五名医科学生、一名医学/博士生、六名K奖获得者、四名 博士后实习生，肺科研究员，心脏病研究员。私家侦探目前指导 七名初级教员。总体而言，我们的计划既是多学科的-雇用 化学、生物化学、分子和细胞生物学、动物生理学等--以及翻译 将基础科学家与内科科学家配对。我们的团队和学员完成了NHLBI/NIH 通过包括非裔美国人、拉丁裔、亚裔和高加索人来实现多样性的使命 会员。我们的计划通过以下方式实现NHLBI战略愿景的所有四个目标：a)阐明 人类生物学的新的外体方面；b)通过新的治疗方法减少人类疾病 针对胞外体途径的发展；c)发展劳动力和动物模型 外切体资源；d)将外切体研究转化为人类疾病。

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.