Injury, inflammation & repair: effect on developing lung

(申请人摘要)本SCOR提案的目标是将Basic和 研究损伤、炎症机制的临床研究方法 和修复发育中的肺，这是慢性肺病发病的基础 婴儿期肺部疾病(CLD)。利用基因打靶技术在动物中的应用 CLD样损伤的模型，研究人员的目标是识别和分析 特定的效应分子改变发育中的细胞行为。项目1 利用糖皮质激素缺乏(促肾上腺皮质激素释放)的小鼠模型 激素基因靶向缺失)研究糖皮质激素反应 在狭窄的发育过程中对正常肺泡形成至关重要的分子 窗户。项目2研究蛙皮素样肽(BLP)在肺中的作用 高氧小鼠模型肺泡化的炎症和破坏 并在临床研究中检查了BLP如何可以用来预测 新生儿呼吸机后慢性阻塞性肺疾病的发生率和严重程度。项目3雇用 肺靶向结构性和诱导性血红素加氧酶-1(HO-1)基因 表达小鼠模型探讨该酶的调控作用 导致CLD样损伤的促炎途径。项目4利用 Syndecan-1和Syndecan-4基因缺失小鼠研究损伤相关诱导 而Syndecans的脱落可能会导致炎症，修复不良， 对感染和异常肺泡和血管的易感性增加 慢性阻塞性肺疾病婴儿肺部的发育。项目5探索 低氧、高氧和感染导致呼吸道增强的机制 使用已建立的呼吸道炎症模型的高反应性。每个人 项目将与动物模型核心(核心B)密切合作 它将(I)协调各种转基因和 将由项目调查人员共享的基因敲除小鼠，(Ii)维护和 协调高氧和低氧动物模型，以及(Iii)协调和 促进DNA微阵列分析肺损伤和炎症 老鼠。临床和生物统计学核心(核心A)将密切合作 与所有SCOR研究人员一起(I)制定可测试的临床假设 基于实验室研究的见解，(Ii)提供样本和临床数据 来自有CLD风险的呼吸机新生儿，以及(Iii)产生统计数据 分析和研究设计。核心D，管理核心，将协调 这些跨学科的努力，管理资金的分配和努力 并创建一个凝聚力强、高度协作的SCOR研究社区。这个 这一综合方法的长期目标是促进新的 慢性阻塞性肺疾病的防治方法。

(Applicant's Abstract) The goal of this SCOR proposal is to combine basic and clinical research approaches to investigate mechanisms of injury, inflammation and repair of the developing lung that underlie the pathogenesis of chronic lung disease (CLD) of infancy. Using gene targeting approaches in animal models of CLD-like injury, the investigators aim to identify and analyze how specific effector molecules alter developmental cellular behaviors. Project 1 utilizes a mouse model of glucocorticord deficiency (corticotrophin-releasing hormone gene targeted deletion) to investigate glucocorticord-responsive molecules critical for normal alveolarization during a narrow developmental window. Project 2 investigates the role of bombesin-like peptide (BLP) in lung inflammation and disruption of alveolarization in a mouse model of hyperoxic injury and in clinical studies examines how BLP may be used to predict the incidence and severity of CLD in newborn ventilated infants. Project 3 employs lung-targeted constitutive and inducible heme oxygenase-1 (HO-1) gene expression mouse models to explore the role of this enzyme in modulating pro-inflammatory pathways that lead to CLD-like injury. Project 4 utilizes syndecan-1 and syndecan-4 null mice to study how injury-associated induction and shedding of syndecans could contribute to the inflammation, poor repair, increased susceptibility to infection and abnormal alveolar and vascular development seen in the lungs of infants with CLD. Project 5 explores mechanisms by which hypoxia, hyperoxia, and infection lead to enhanced airway hyper-responsiveness using established models of airway inflammation. Each project will have close collaboration with the animal model core (Core B) which will (i) coordinate animal breeding of the various transgenic and knockout mice to be shared by project investigators, (ii) maintain and orchestrate hyperoxic and hypoxic animal models, and (iii) coordinate and facilitate the DNA microarray to analyze lung injury and inflammation in the mouse. The Clinical and Biostatistical Core (Core A) will collaborate closely with all SCOR investigators to (i) formulate testable clinical hypotheses based on insights from lab studies, (ii) provide samples and clinical data from ventilated newborns at risk for CLD, and (iii) generate statistical analyses and study designs. Core D, Administrative Core, will orchestrate these interdisciplinary efforts, manage the distribution of funds and efforts and create a cohesive, highly collaborative SCOR research community. The long-term goal of this integrated approach is to facilitate development of new methods for the prevention and treatment of CLD.