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

项目摘要慢性阻塞性肺疾病（COPD）是全球死亡和当前死亡的第四个主要原因治疗仅治疗症状，但不能停止这种使人衰弱的疾病的进展。 COPD定义为临床综合征以呼吸道症状，不可逆的气流限制和肺部为特征结构异常（肺气肿和/或气道疾病）。 COPD肺的关键病理特征是慢性炎症，组织破坏和血管异常。新兴数据指向中心 COPD发病机理的肺微举行渐进的肺部破坏。该提议涉及定义血管机制的关键需求 COPD的发病机理提供了一种治疗路径，并降低了数百万的发病率和死亡率患有这种疾病的患者。我们已经表明，在人类COPD肺组织中，钥匙表达的表达丧失内皮标志物暗示血管功能障碍，与疾病严重程度有关。我们也是在肺气肿的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）治疗的细分市场改善了肺气肿。这些数据支持 “肺血管生态位”对肺泡毛皮单元的完整性至关重要的新颖概念，但这些结果是第一个表明重建肺内皮隔室的结果可以改变隆重状态的过程。在从浓度肺，富含亮氨酸的α-2-的PCEC中糖蛋白-1（LRG1）是一个顶部的上调基因。 LRG1是一种与TGF-𝜷结合的分泌糖蛋白在EC中，辅助受体会扭曲其信号传导，以引起几种疾病状态的异常血管。在此提案中，我们假设超过PCEC衍生的LRG1级别 PCEC导致血管生态位失调，随之而来的是肺气肿的发展。目的决定雇用裸露过多的 3，和到策略成功的康奈尔资源 1，威尔 PCEC LRG1通过成人内皮中缺乏LRG1的一般修饰的小鼠的使用。这些老鼠会对于香烟烟雾和弹性酶引起的肺气肿模型。 AIM 2将定义人血管化肺器官模型中肺泡毛细血管网络上LRG1的水平。目的将确定LRG1信号传导的扰动在多大程度上阻止鼠中的肺气肿表型人类模型系统使用针对LRG1的中和抗体。这些研究将发现机制促进肺血管生态位的归一化允许牙槽修复并发展新颖治疗COPD。该建议在成为职业发展计划中起着核心作用独立的研究者关注COPD发病机理中血管功能障碍。威尔医学是执行该培训计划的理想环境，因为它具有丰富的科学以及早期研究人员强烈心态的往绩。 t t