The role of endothelial derived Leucine-Rich Alpha-2-Glycoprotein 1 (LRG1) in the pathogenesis of COPD

项目总结 慢性阻塞性肺疾病(COPD)是全球第四大死亡原因，目前 治疗只能治疗症状，但不能阻止这种令人衰弱的疾病的发展。慢性阻塞性肺病被定义为 以呼吸道症状为特征的临床综合征，气流受限是不可逆转的，而且是肺性的 结构异常(肺气肿和/或呼吸道疾病)。COPD肺的主要病理特征是 慢性炎症、组织破坏和血管异常。不断涌现的数据表明 肺微血管系统与COPD的发病机制有关，但血管损伤如何导致 进行性肺部破坏。这一建议解决了定义血管发病机制(S)的迫切需要 COPD的发病机制提供了一条治疗途径，并降低了数百万人的发病率和死亡率 患有这种疾病的患者。我们已经证明了在人类COPD肺组织中表达缺失的关键 提示血管功能障碍的内皮标记物意义深远，与疾病严重程度有关。我们也 在肺气肿的小鼠模型中发现了血管功能障碍，并表明恢复肺血管 NICE联合肺毛细血管内皮细胞(PCEC)治疗可改善肺气肿。这些数据支持 “肺血管龛”这一新概念对肺泡-毛细血管单位的完整性至关重要，但 这些结果首次表明，重建肺内皮细胞间隔可以改变 肺气肿的病程。在肺气肿肺分离的PCECs中，富含亮氨酸的α-2- 糖蛋白-1(LRG1)是一个上调表达的基因。Lrg1是一种与转化生长因子-𝜷结合的分泌型糖蛋白。 一种辅助受体，在内皮细胞中扭曲它们的信号，在几种疾病状态下导致异常血管。 在这项建议中，我们假设PCEC来源的LRG1水平过高会改变血管内皮细胞的稳态功能 PCECs导致血管生态位失调，从而导致肺气肿的发展。目标 确定 用人 裸露 过份 3、 和 至 策略 成功 康奈尔大学 资源 1、Will PCEC LRG1通过以下途径促进小鼠肺气肿发病的机制(S) 缺乏LRG1的转基因小鼠在成人血管内皮细胞中的应用。这些老鼠将会是 香烟烟雾和弹力酶诱导的肺气肿模型。目标2，将定义 人肺血管化肺器官模型肺泡-毛细血管网络上LRG1的水平。目标 将确定LRG1信号的扰动在多大程度上阻止小鼠的肺气肿表型 使用LRG1中和抗体的人体模型系统。这些研究将揭示 促进肺血管龛正常化以允许肺泡修复和开发新的 治疗慢性阻塞性肺疾病。这项提议在职业发展计划中起着核心作用， 独立研究人员专注于COPD发病机制中的血管功能障碍。威尔 医学是实施这一培训计划的理想环境，因为它具有丰富的科学性 以及强大的早期调查人员导师的强大业绩记录。 T T

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and current therapy only treats symptoms but cannot stop progression of this debilitating disease. COPD is defined as a clinical syndrome characterized by respiratory symptoms, airflow limitation that is irreversible, and pulmonary structure abnormalities (emphysema and/or airways disease). The key pathologic features of COPD lungs are chronic inflammation, tissue destruction, and vascular abnormalities. Emerging data points to the centrality of the lung microvasculature to the pathogenesis of COPD but little is known of how vascular damage leads to progressive lung destruction. This proposal addresses the critical need to define the mechanism(s) of vascular pathogenesis of COPD to provide a therapeutic path forward and to reduce the morbidity and mortality for millions of patients with this disease. We have shown that in human COPD lung tissue loss of expression of key endothelial markers, suggestive of vascular dysfunction, is profound and linked to disease severity. We also found vascular dysfunction in a murine model of emphysema and showed that restoring the pulmonary vascular niche with pulmonary capillary endothelial cell (PCEC) therapy ameliorated emphysema. These data support the novel concept that the “pulmonary vascular niche” is critical to the integrity of the alveolar-capillary unit, but these results are the first to show that re-establishing the pulmonary endothelial compartment can change the course of the emphysematous state. In PCECs isolated from emphysematous lung, leucine-rich alpha-2- glycoprotein-1 (Lrg1) was a top up-regulated gene. LRG1, is a secreted glycoprotein that binds to the TGF-𝜷 accessory receptor that in ECs distorts their signaling to cause aberrant blood vessels in several disease states. In this proposal, we hypothesize that excessive levels of PCEC-derived LRG1 alters homeostatic functions of PCECs leading to a dysregulated vascular niche whereby the development of emphysema ensues. Aim determine employing exposed excessive 3, and to strategies successful Cornell resources 1, will the mechanism(s) by which PCEC LRG1 promotes he pathogenesis of emphysema in mice by the use of genetically modified mice lacking Lrg1 in the adult endothelium. These mice will be to the cigarette smoke and elastase induced models of emphysema. Aim 2, will define the impact of levels of LRG1 on the alveolar-capillary network in human vascularized lung organoid models. Aim will determine the extent to which perturbations of LRG1 signaling blocks the emphysema phenotype in murine human model systems using a neutralizing antibody against LRG1. These studies will uncover mechanisms promote normalization of the pulmonary vascular niche o allow alveolar repair and the development of novel to treat COPD. This proposal plays a central role in a career development plan for becoming a independent investigator focused on vascular dysfunctions in the pathogenesis of COPD. Weill Medicine is an ideal environment in which to execute this training plan because of its rich scientific and the strength of the track record of strong mentorship of early-stage investigators. t t