Molecular Targets in Bronchopulmonary Dysplasia

描述（由申请人提供）： 长期目标是更好地了解导致需要机械通气的早产儿发生支气管肺发育不良（BPD）的事件进展，并测试类维生素A治疗预防BPD发生的疗效。早产儿肺在结构上不成熟，当受到通气的机械力时，在细胞和结构水平上受到损伤。牵张介导的损伤阻断了新生儿肺的正常发育模式，并导致气体交换能力的丧失。以前的研究表明，结构蛋白弹性蛋白是肺泡发育所需的，并在BPD肺中异常组装成纤维，并且肺泡肌成纤维细胞表型和分布在BPD中改变。目前正在人体试验中测试类维生素A在减轻有BPD风险的通气早产儿肺损伤方面的功效，并且已知类维生素A调节发育中的肺中的弹性蛋白基因表达。本提案的第一个具体目的是测试类维生素A在减弱狒狒BPD模型中BPD发展的功效，并确定类维生素A对通气早产儿弹性纤维沉积和组装的影响。该模型提供了高度受控的治疗方案，因此可用于严格测试治疗方式。将在妊娠125天分娩的早产狒狒胎仔分配至类维生素A处理组或溶媒组，然后进行6-14天的标准处理。生理指标、肺结构的形态测定分析以及弹性纤维组装和损伤的分子分析将用于评估类维生素A的作用。第二个目的是确定其他实验治疗对肺泡肌成纤维细胞分布和弹性纤维组装的影响，因为我们提出这些是肺泡发育的重要指标。第三个目标是使用基因阵列技术来识别由机械通气引起的基因表达的变化，并“挖掘”基因表达谱，以开发BPD的分子特征。这一目标还将确定与肺泡发育相关的表达谱基因，以及BPD特异性治疗的下游靶点。这些研究将在联合会内部高度互动，并为整个科学界提供基因表达数据。

DESCRIPTION (provided by applicant): The long-term objectives are to better understand the progression of events leading to the development of bronchopulmonary dysplasia (BPD) in premature neonates requiring mechanical ventilation, and to test the efficacy of retinoid treatments in preventing the development of BPD. The premature lung is structurally immature and is subject to injury at the cellular and architectural levels when subjected to the mechanical forces of ventilation. Stretch-mediated injury blocks the normal developmental pattern of the neonatal lung and results in loss of gas-exchange capacity. Previous studies have shown that the structural protein elastin is required for alveolar development and is abnormally assembled into fibers in the BPD lung, and that the alveolar myofibroblast phenotype and distribution is altered in BPD. Retinoids are currently being tested in human trials for efficacy in abating lung injury in the ventilated premature neonate at risk for BPD, and are known to regulate elastin gene expression in the developing lung. The first specific aim of this proposal is to test the efficacy of retinoids in attenuating the development of BPD in the baboon model of BPD, and to determine the effects of retinoids on elastic fiber deposition and assembly in the ventilated premature neonate. This model offers highly controlled treatment regimens and therefore can be used to critically test therapeutic modalities. Preterm baboon fetuses delivered at 125 d of gestation will be assigned to retinoid treatment or vehicle and then subjected to the standard treatments for 6-14 days. Physiologic indices, morphometric analysis of lung structure, and molecular analyses of elastic fiber assembly and injury will be used to assess retinoid effects. The second aim is to determine the effects of other experimental treatments on alveolar myofibroblast distribution and elastic fiber assembly, as we propose these are important indices of alveolar development. The third aim is to use gene array technology to identify changes in gene expression resulting from mechanical ventilation, and to "mine" gene expression profiles with the goal of developing a molecular signature for BPD. This aim will also identify genes with expression profiles associated with alveolar development, and downstream targets of specific therapies for BPD. These studies will be highly interactive within the Consortium and provide gene expression data for the scientific community at large.