A2: MATRIX: BIOLOGY & PATHOBIOLOGY OF PRE & POST NATAL ELASTIC TISSUES

本提案的目的是检验以下假设： 具有特异性影响肺的基因突变的转基因小鼠 弹性蛋白会改变气道平滑肌的收缩 性能和更容易受到高氧-和硝酸 氧化诱导的气道功能障碍。 四种原球茎的表型 (TP)小基因构建体揭示了弹性组织的紊乱， 表现出发育调节和组织特异性。后代 TP-2在5-7周龄时死亡， 呼吸窘迫和肺气肿 TP-4结构模具之间 7-9月龄伴出血和组织病理学 显示上行动脉内侧弹性纤维异常 主动脉，符合升主动脉瘤的易感性 Th-l和TP-3构建体不产生异常弹性组织 表型研究将分为三个具体目标：#1： 确定血管和气道的发育调节 弹性蛋白转基因小鼠平滑肌功能研究 突变; #2：确定气道功能效应和肺 新生儿期高氧暴露对弹性蛋白的损伤; 和#3：确定气道功能效应和肺弹性蛋白 新生儿期吸入NO的损伤。等长张力 气道和血管平滑肌的测量将 就业。 肺功能将通过压力-容积测定 通过光学显微镜测量的弯曲和弹性蛋白完整性， 扫描EM组织学和测量总弹性蛋白合成。 将通过组织学评估肺部炎症的指标， 气管吸出液中白色细胞成分和炎性 细胞蛋白酶活性

The objective of this proposal is to test the hypotheses that transgenic mice with gene mutations specifically affecting lung elastin will have altered airway smooth muscle contractile properties and be more susceptible to hyperoxia- and nitric oxide-induced airway dysfunction. Phenotypes of four tropoprom (TP) minigene constructs reveal disorders of elastic tissue which appear developmentally regulated and tissue-specific. Progeny from founder lines TP-2 die at 5-7 weeks of age associated with respiratory distress and emphysema. TP-4 constructs die between 7-9 months of age with hemorrhage and histopathology demonstrating abnormal medial elastic fibers in the ascending aorta,. consistent with predisposition to ascending aortic aneurysm. Th-l and TP-3 constructs do not develop abnormal elastic tissue phenotypes. Studies will be divided into three specific aims: #1: Determine the developmental regulation of vascular and airway smooth muscle function in transgenic mice with elastin gene mutations; #2: Determine the airway functional effect and lung elastin damage of hyperoxic exposure during the newborn period; and #3: Determine the airway functional effect and lung elastin damage of inhaled NO during the newborn period. Isometric force measurements of airway and vascular smooth muscle will be employed. Lung function will be determined by pressure-volume curves and elastin integrity measured by light microscopy, scannmg EM histology, and measurement of total elastin synthesis. Indices of lung inflammation will be assessed by histology, tracheal aspirate fluid white cell composition and inflammatory cell proteinase activity.