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

这项提议的目的是检验以下假设 具有肺部特异基因突变的转基因小鼠 弹性蛋白会改变呼吸道平滑肌的收缩 而且更容易受到高氧和硝酸盐的影响 氧化物引起的呼吸道功能障碍。四种催产素的表型 (TP)迷你基因结构揭示了弹性组织的紊乱 表现出发育受控和组织特异性。子代 来自创立者的TP-2系在5-7周龄死亡与 呼吸窘迫和肺气肿。TP-4构造物在 7-9个月龄，伴有出血和组织病理学 提示升支内侧弹力纤维异常 大动脉，。与升主动脉瘤的易感性一致。 TH-L和TP-3结构不会形成异常弹性组织 表型。研究将分为三个具体目标：#1： 确定血管和呼吸道的发育规律 转弹性蛋白基因小鼠的血管功能研究 突变；#2：确定呼吸道功能影响和肺 新生儿期高氧暴露对弹性蛋白的损伤； 和#3：确定呼吸道功能效应和肺弹性蛋白 新生儿期吸入NO的损害。等轴向力 呼吸道和血管平滑肌的测量将是 受雇的。肺功能将由压力-容量决定 通过光学显微镜测量曲线和弹性蛋白完整性， 扫描EM组织学，并测量总弹性蛋白合成。 肺部炎症指数将通过组织学进行评估， 气管抽吸液中白细胞组成与炎症 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.