Role of lung WWOX deficiency in vascular leak during lung injury

肺WWOX缺乏在肺损伤期间血管渗漏中的作用

基本信息

批准号：
10456302
负责人：
Sunit Singla
金额：
$ 17.42万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456302
关键词：
Actins Acute Acute Respiratory Distress Syndrome Address Alveolar Animal Model Blood Vessels Cell membrane Cell surface Chromosome Fragile Sites Chromosome Fragility Complex Critical Illness Data Endothelial Cells Endothelium Event Floods Genotoxic Stress Human Human Genome IL8 gene In Vitro JUN gene Knowledge Lipopolysaccharides Lung Maintenance Membrane Modeling Molecular Morbidity - disease rate Mus Pathogenesis Patients Physicians Play Predisposition Process Public Health Publishing Pulmonary Edema Respiratory Failure Role Scientist Sepsis Smoker Survivors Tumor Suppressor Proteins United States Vascular Permeabilities Work base cell type cigarette smoke cigarette smoke-induced epidemiology study exposure to cigarette smoke ezrin in vivo lung injury neutrophil non cardiogenic pulmonary edema non-smoker novel strategies overexpression protective effect recruit respiratory sepsis induced ARDS

Actins Acute Acute Respiratory Distress Syndrome Address Alveolar Animal Model Blood Vessels Cell membrane Cell surface Chromosome Fragile Sites Chromosome Fragility Complex Critical Illness Data Endothelial Cells Endothelium Event Floods Genotoxic Stress Human Human Genome IL8 gene In Vitro JUN gene Knowledge Lipopolysaccharides Lung Maintenance Membrane Modeling Molecular Morbidity - disease rate Mus Pathogenesis Patients Physicians Play Predisposition Process Public Health Publishing Pulmonary Edema Respiratory Failure Role Scientist Sepsis Smoker Survivors Tumor Suppressor Proteins United States Vascular Permeabilities Work base cell type cigarette smoke cigarette smoke-induced epidemiology study exposure to cigarette smoke ezrin in vivo lung injury neutrophil non cardiogenic pulmonary edema non-smoker novel strategies overexpression protective effect recruit respiratory sepsis induced ARDS

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项目摘要

Project Summary/Abstract Acute respiratory distress syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and is seriously debilitating for many survivors. Specific ARDS therapies do not currently exist, and efforts to reduce its burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The cardinal, morbidity-producing feature of ARDS is non-cardiogenic pulmonary edema resulting from pulmonary vascular barrier disruption with consequent alveolar flooding, and respiratory failure. The conceptual underpinning for these events consists of cytoskeletal contraction of pulmonary endothelial cells (ECs) leading to the formation of paracellular gaps. Novel strategies which reduce the vascular permeability and lung edema of ARDS are desperately needed. The objective of this proposal is to determine the contribution of the tumor suppressor WWOX to the pathobiological processes associated with ARDS. WWOX resides at the second most active common chromosomal fragile site in the human genome, making it highly susceptible to genotoxic stress such as that which occurs during cigarette smoke and other toxic respiratory exposures. Data detailed in this application suggests that 1) loss of WWOX occurs in the lung during cigarette smoke exposure, and this event may at least partly explain an increased susceptibility for severe ARDS in smokers versus nonsmokers observed in currently emerging evidence from epidemiologic studies, and 2) WWOX exerts potent EC barrier-protective effects during both in vivo and in vitro lipopolysaccharide (LPS)-induced ARDS. This project aims to 1) determine the significance of EC WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes EC barrier protection and 3)Establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.

项目摘要/摘要急性呼吸窘迫综合征（ARDS）是一种危害估计的疾病仅在美国，每年有20万名患者，大约杀死75,000例，并且严重为许多幸存者衰弱。目前不存在特定的ARDS疗法，并为减轻负担的限制是由于分子的不完整表征其发病机理的基础机制。 ARDS的主要发病率特征是肺血管屏障破坏引起的非心脏病性肺水肿因此肺泡洪水和呼吸衰竭。这些概念上的基础事件包括肺内皮细胞（EC）的细胞骨架收缩，导致副细胞间隙的形成。新的策略，可降低血管渗透性和迫切需要ARDS的肺水肿。该提议的目的是确定肿瘤抑制剂WWOX对与之相关的病理生物学过程的贡献 ARDS。 WWOX位于第二个最活跃的常见染色体脆弱位点人类基因组，使其高度容易受到遗传毒性应激，例如发生在香烟烟和其他有毒呼吸道暴露期间。此应用程序中详细介绍的数据表明1）在烟烟暴露期间，肺部发生WWOX的丧失，这事件至少可以部分解释吸烟者对严重ARD的敏感性增加非吸烟者在流行病学研究的当前新兴证据中观察到，2） WWOX在体内和体外都发挥有效的EC屏障保护作用脂多糖（LPS）诱导的ARDS。该项目的目的是1）确定 EC WWOX在鼠ARDS中的表达，2）定义了WWOX的分子机制促进EC障碍保护和3）建立基于WWOX的治疗的概念基础在香烟中，败血症引起的弧形。