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

内皮源性富含亮氨酸的 Alpha-2-糖蛋白 1 (LRG1) 在 COPD 发病机制中的作用

基本信息

批准号：
10507591
负责人：
Alexandra Christin Racanelli
金额：
$ 16.85万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507591
关键词：
Acute Address Adult Airway Disease Alveolar Binding Biological Models Blood Vessels Blood capillaries Capillary Endothelial Cell Cause of Death Cell Compartmentation Cell Therapy Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Cigarette smoke-induced emphysema Clinical Data Development Development Plans Disease Elastases Endothelial Cells Endothelium Environment Extracellular Matrix Genes Glycoproteins Goals Growth Factor Homeostasis Human Impairment Inflammation Injury Leucine Link Lung Medicine Mentorship Modeling Morbidity - disease rate Mus Natural regeneration Organ Organoids Pathogenesis Pathologic Patients Permeability Phenotype Play Pulmonary Emphysema Pulmonary Inflammation Research Personnel Resources Respiratory Signs and Symptoms Role Severities Severity of illness Signal Transduction Structure Structure of parenchyma of lung Suggestion Syndrome Testing Therapeutic Tissues Training Vascular Diseases airway obstruction career development cigarette smoke density experimental study exposure to cigarette smoke human model improved lung injury mortality mouse model neutralizing antibody new therapeutic target novel novel strategies pulmonary function receptor repaired response response to injury symptom treatment vascular abnormality

项目摘要

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

项目概要慢性阻塞性肺疾病（COPD）是目前全球第四大死亡原因治疗只能治疗症状，但不能阻止这种使人衰弱的疾病的进展。以呼吸道症状、不可逆的气流受限和肺部疾病为特征的临床综合征 COPD 肺部的主要病理特征是结构异常（肺气肿和/或气道疾病）。新出现的数据表明了慢性炎症、组织破坏和血管异常的重要性。肺微血管系统与 COPD 的发病机制有关，但对于血管损伤如何导致该提案解决了定义血管机制的迫切需要。慢性阻塞性肺病的发病机制提供治疗途径并降低数百万人的发病率和死亡率我们已经证明，在人类 COPD 肺组织中，关键蛋白的表达缺失。提示血管功能障碍的内皮标记物具有深远的意义，并且与疾病的严重程度相关。在小鼠肺气肿模型中发现血管功能障碍，并表明恢复肺血管这些数据支持肺毛细血管内皮细胞（PCEC）治疗可改善肺气肿。 “肺血管生态位”对于肺泡毛细血管单位的完整性至关重要的新概念，但是这些结果首次表明重建肺内皮室可以改变从肺气肿肺中分离出富含亮氨酸的 α-2- 的 PCEC。糖蛋白-1 (Lrg1) 是最上调的基因，是一种与 TGF-𝜷 结合的分泌型糖蛋白。 EC 中的辅助受体会扭曲其信号传导，导致几种疾病状态下的血管异常。在此提案中，我们研究了 PCEC 衍生的 LRG1 水平过高会改变 PCEC 导致血管生态位失调，从而导致肺气肿的发生。决定雇用裸露过多的 3、和到策略成功的康奈尔大学资源 1、会 PCEC LRG1 促进小鼠肺气肿发病的机制使用成年内皮细胞中缺乏Lrg1的转基因小鼠将获得这些小鼠。目标2，将定义对香烟烟雾和弹性蛋白酶诱发的肺气肿模型的影响。人血管化肺类器官模型中肺泡毛细血管网络中 LRG1 的水平。将确定 LRG1 信号传导干扰阻断小鼠肺气肿表型的程度使用针对 LRG1 的中和抗体的人类模型系统将揭示其机制。促进肺血管生态位正常化 o 允许肺泡修复和新功能的开发该提案在成为一名慢性阻塞性肺病患者的职业发展计划中发挥着核心作用。一位独立研究者专注于慢性阻塞性肺病发病机制中的血管功能障碍。医学因其丰富的科学性而成为执行该训练计划的理想环境。以及早期研究人员强有力的指导记录的强度。 t t