REGULATION OF GROWTH ARREST IN HYPEROXIC NEONATAL LUNG

高氧新生儿肺生长停滞的调节

• 批准号: 2027141
• 负责人: Sharon Ann McGrath-Morrow
• 金额: $ 8.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2027141
• 关键词: DNA repair; bronchopulmonary dysplasia; cell growth regulation; cyclins; genetic regulation; growth inhibitors; histogenesis; hyperoxia; laboratory mouse; newborn animals; ubiquitin

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.

描述 （改编自申请人的摘要）未成熟的肺暴露 氧气张力会改变牙槽组织和肺部的生长 发育中的肺中的脉管系统（1,2）。 在 新生儿时期是发展的重要因素 支气管肺发育不良（BPD）最常见的慢性肺形式 婴儿和儿童的疾病。 BPD婴儿的肺部生长为 正常牙槽繁殖失败（3）可能会受到损害 继发于新生儿时期高氧早期暴露的继发性。 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，高氧化暴露延迟了DNA合成 新生儿鼠肺（5,6）。 调节的基本分子机制 暴露于高氧的新生儿肺中的细胞生长停滞尚未 广泛评估。 在此提案中，申请人假设 新生儿肺高氧继发于高氧的生长停滞与 已知和新基因的调节。 使用减法杂交A 分离出新型的泛素偶联酶2（UBC-2），发现为 在高氧期间明显下调。 申请人假设 新生儿肺高氧继发于高氧的生长停滞与 泛素结合酶的下降调节所必需的 特异性细胞周期蛋白抑制剂的降解。 这种新颖的UBC-2酶是 与Rad6同源于酿酒酵母中参与DNA的酶 修复（7,8）和人UBC2涉及细胞周期蛋白降解的酶 抑制剂P27（9）。 下调这种新型的泛素酶基因 提出了细胞周期蛋白抑制剂在调节高氧化生长中的作用 在新生儿肺部被捕。 该基因也可能在DNA修复中起作用 细胞根据其与Rad6的同源性暴露于高氧。 下调 泛素途径导致细胞周期蛋白抑制剂的水平增加 导致细胞生长停滞可能导致肺泡受损 BPD的婴儿中发现的生长。 除了评估 这种新型的泛素酶在生长停滞中 减法杂交可能在细胞周期调节或 将评估有丝分裂基因。