REGULATION OF GROWTH ARREST IN HYPEROXIC NEONATAL LUNG

描述 (改编自申请人的摘要)未成熟的肺暴露于高水平 氧分压可改变肺泡组织和肺组织的生长 发育中的肺中的血管构筑(1，2)。高氧暴露在人体内 新生儿期是影响胎盘发育的重要因素。 支气管肺发育不良(BPD)是慢性肺的最常见形式 婴幼儿的疾病。BPD婴儿的肺生长发育 肺泡正常增殖功能受损(3)可能 继发于新生儿期早期暴露的高氧血症。 已知高氧可导致培养中的肺泡细胞生长停滞(4)。 研究还表明，高氧暴露会延迟脑组织中DNA的合成 新生小鼠肺(5，6)。潜在的分子调控机制 高氧暴露下新生儿肺细胞生长停滞的研究 经过广泛评估。在这份提案中，申请人假设 新生儿肺内高氧继发的生长停滞与 对已知的和新的基因的调节。使用消减杂交技术 新的泛素结合酶2(UBC-2)被分离出来，发现是 在高氧期间显著下调。申请人假设 新生儿肺内高氧继发的生长停滞与 泛素结合酶的下调是细胞生长所必需的 特定的细胞周期蛋白抑制剂的降解。这种新型的UBC-2酶是 与酿酒酵母中与DNA有关的酶RAD6同源 修复(7，8)和人Ubc2参与周期蛋白降解的酶 抑制物p27(9)。这种新的泛素酶基因的下调 提示细胞周期蛋白抑制剂在高氧生长调节中的作用 新生儿肺部停滞。该基因也可能在DNA修复中发挥作用 基于其与RAD6的同源性，暴露于高氧环境的细胞。降级调节 泛素途径导致细胞周期蛋白抑制物水平升高 导致细胞生长停滞可能导致肺泡受损 在患有BPD的婴儿中发现生长。除了评估的作用外， 这种新的泛素酶在生长过程中阻止了其他基因的生长 消减杂交可能在细胞周期调节或 将对有丝分裂进行评估。

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.