REGULATION OF GROWTH ARREST IN HYPEROXIC NEONATAL LUNG

描述 （改编自申请人摘要）未成熟肺暴露于高 氧张力可以改变肺泡组织和肺组织的生长， 在发育中的肺中的脉管系统（1，2）。 高氧暴露 新生儿期是一个重要因素的发展， 支气管肺发育不良（BPD）是慢性肺 婴儿和儿童的疾病。 患有BPD的婴儿的肺生长 可能伴有正常肺泡增殖失败（3） 继发于新生儿期早期接触高氧。 已知高氧会导致培养物中肺泡细胞的生长停滞（4）。 研究还表明，高氧暴露延迟DNA合成， 新生鼠肺（5，6）。 潜在的分子机制调节 暴露于高氧的新生儿肺中的细胞生长停滞还没有被发现。 广泛评价。 在本提案中，申请人假设， 新生儿肺中继发于高氧的生长停滞与 已知和新基因的调控。 使用消减杂交a 一种新的泛素结合酶2（Ubc-2）被分离并发现是 在高氧时显著下调。 申请人假设， 新生儿肺中继发于高氧的生长停滞与 下调泛素结合酶的必要性， 特异性细胞周期蛋白抑制剂的降解。 这种新的Ubc-2酶是 与RAD 6同源，RAD 6是酿酒酵母中涉及DNA的酶 修复（7，8）和人Ubc 2，一种参与细胞周期蛋白降解的酶 抑制剂p27（9）。 这种新的泛素酶基因的下调 表明细胞周期蛋白抑制剂在高氧生长调节中的作用 新生儿肺骤停。 该基因也可能在DNA修复中起作用， 暴露于高氧的细胞，基于其与RAD 6的同源性。 下调 泛素途径导致细胞周期蛋白抑制剂水平增加 导致细胞生长停滞可能会导致受损的肺泡 在BPD婴儿中发现的生长。 除了评估 这种新的泛蛋白酶在生长停滞的其他基因确定的 可能在细胞周期调节中起作用的消减杂交， 将评价有丝分裂。

DESCRIPTION (Adapted from the applicant's abstract) Exposure of immature lung to high oxygen tensions can alter growth of alveolar tissue and pulmonary vasculature in the developing lung (1,2). Hyperoxic exposure in the neonatal period is an important factor in the development of bronchopulmonary dysplasia (BPD) the most common form of chronic lung disease in infants and children. Lung growth of infants with BPD is impaired with failure of normal alveolar multiplication (3) possibly secondary to the early exposure of hyperoxia in the neonatal period. Hyperoxia is known to cause growth arrest in alveolar cells in culture (4). Studies have also shown that hyperoxic exposure delays DNA synthesis in neonatal murine lung (5,6). The underlying molecular mechanisms regulating cellular growth arrest in neonatal lung exposed to hyperoxia have not been extensively evaluated. In this proposal the applicant hypothesizes that growth arrest secondary to hyperoxia in the neonatal lung is associated with the regulation of known and novel genes. Using subtractive hybridization a novel ubiquitin conjugating enzyme 2 (Ubc-2) was isolated and found to be markedly downregulated during hyperoxia. The applicant hypothesizes that growth arrest secondary to hyperoxia in the neonatal lung is associated with the down regulation of ubiquitin conjugating enzymes necessary for the degradation of specific cyclin inhibitors. This novel Ubc-2 enzyme is homologous to RAD6 an enzyme in Saccharomyces cerevisiae involved in DNA repair (7,8) and human Ubc2 an enzyme involved in degradation of the cyclin inhibitor p27 (9). Down regulation of this novel ubiquitin enzyme gene suggests a role for cyclin inhibitors in the regulation of hyperoxic growth arrest in neonatal lung. This gene may also have a role in DNA repair in cells exposed to hyperoxia based on its homology to RAD6. Down regulation of the ubiquitin pathway resulting in increase levels of cyclin inhibitors leading to cellular growth arrest could contribute to the impaired alveolar growth found in infants with BPD. In addition to evaluating the role of this novel ubiquitin enzyme in growth arrest other genes identified by subtractive hybridization which may have a role in cell cycle regulation or mitogeneses will be evaluated.