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

项目摘要 慢性阻塞性肺疾病（COPD）是全球第四大死亡原因， 治疗仅治疗症状，但不能阻止这种使人衰弱的疾病的进展。COPD定义为 以呼吸道症状、不可逆的气流受限和肺部感染为特征的临床综合征 结构异常（肺气肿和/或气道疾病）。COPD肺部的主要病理特征是 慢性炎症、组织破坏和血管异常。新出现的数据表明， 肺微血管系统与COPD的发病机制有关，但对血管损伤如何导致 进行性肺损伤该提案解决了定义血管内凝血机制的迫切需要。 研究COPD的发病机制，为数百万人提供治疗途径，降低发病率和死亡率， 患这种病的病人。我们已经表明，在人COPD肺组织中，关键的 提示血管功能障碍的内皮标志物是深刻的，并与疾病的严重程度有关。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 肺毛细血管内皮细胞（PCEC）治疗改善肺气肿。这些数据支持 新的概念，“肺血管龛”是至关重要的完整性肺泡毛细血管单位，但 这些结果首次表明，重建肺内皮隔室可以改变 肺气肿的病程在从肺气肿肺分离的PCEC中，富含亮氨酸的α-2- 糖蛋白-1（Lrg 1）是一个上调最高的基因。LRG 1是一种分泌型糖蛋白，与TGF-β 1结合， 在内皮细胞中的辅助受体扭曲它们的信号传导，从而在几种疾病状态下引起异常血管。 在这个建议中，我们假设PCEC衍生的LRG 1的过度水平改变了细胞的稳态功能， PCEC导致血管生态位失调，从而导致肺气肿的发展。目的 确定 采用 暴露 过度 3, 和 到 战略 成功 康奈尔 资源 1将 PCEC LRG 1促进小鼠肺气肿发病的机制， 在成年内皮细胞中缺乏Lrg 1的转基因小鼠的应用。这些老鼠将 香烟烟雾和弹性蛋白酶诱导的肺气肿模型。目标2，将定义 在人血管化肺类器官模型中肺泡-毛细血管网络上的LRG 1水平。目的 将确定LRG 1信号传导的扰动阻断鼠肺气肿表型的程度 使用针对LRG 1的中和抗体的人类模型系统。这些研究将揭示 促进肺血管生态位的正常化，使肺泡修复和新的发展 治疗COPD。该提案在职业发展计划中发挥着核心作用， 一名独立研究者专注于COPD发病机制中的血管功能障碍。Weill 医学是一个理想的环境，其中执行这一培训计划，因为它丰富的科学 以及对早期调查人员的良好指导记录。 不 不

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