利用宫内缺氧诱导子鼠CT肺容积表型差异来筛选被甲基化沉默的肺泡发育关键基因

项目名称： 利用宫内缺氧诱导子鼠CT肺容积表型差异来筛选被甲基化沉默的肺泡发育关键基因

项目编号： No.81500001

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 熊曾

作者单位： 中南大学

项目金额： 18万元

中文摘要： 肺泡发育障碍是导致支气管肺发育不良（BPD）的根本原因，非遗传因素(如高氧性肺损伤BPD模型常伴有肺部炎症、纤维化等与肺泡发育无关的因素)对研究结果影响较大，决定肺泡发育最关键的基因至今不明，因此缺乏有效的临床防治措施。申请者发现宫内缺氧BPD模型肺泡发育障碍不伴有明显的炎症及纤维化，且模型鼠肺泡发育受阻受表观遗传学调控，CT肺容积成像能很方便地活体、动态地观察到模型鼠肺泡发育的表型差异。基于此，本项目首次将宫内缺氧BPD模型、CT肺容积成像、肺泡发育细胞模型和遗传学及表观遗传学技术结合起来，以CT容积成像观察宫内缺氧对子鼠肺泡发育的不同影响为切入点，尽可能控制非遗传因素的影响，对被甲基化沉默的肺泡发育关键基因进行筛选及功能鉴定，有望捕获5-8个具有潜在临床应用价值的肺泡发育关键基因，为明晰BPD发病机制，阻断BPD病理过程，促进肺泡发育提供依据，具有重要的理论价值与临床应用前景。

中文关键词： 肺泡发育；新生儿；基因组学；DNA甲基化；表观遗传学

英文摘要： Alveolar developmental abnormality is the primary cause of branchopulmonary dysplasia pathogenesis. The key genes in alveolar formation are poorly understood. There is a dearth of methods to cure the bronchopulmonary dysplasia or prevent its pathogenesis. As the fund applicants, we have found that the fetal-hypoxia-treated mouse model to study the alveolar development pausing in the pathogenesis of BPD would not associate with the obvious inflammation and fibrosis. And we have evidence to show that the alveolar formation pausing in the mouse model is controlled by the epigenetic mechanism. In addition the lung volumetric CT imaging can facilitate the dynamic in vivo observation on the phenotypic differences in the alveolar development among the model mice. Based on these facts we innovatively integrate the BPD mouse model induced by fetal hypoxia with the lung volumetric CT imaging, a brand-new cell model studying the alveolar development and those genetic/epigenetic technologies to monitor the alveolar development process in the mouse-pup models treated with fetal hypoxia, and in this study we will do our best to limit the ambiguous effects from the non-genetic aspects. Through these strategies aboved we wish to select 5-8 key genes which are repressed via methylation modification in the alveolar development and identify their function respectively. The BPD pathogenesis mechanism we elucidated in this study may give us a more sophisticated theory to understand the alveolar development process and eventually provide us with the intellectual capital that fuels the forward thrust of the therapeutic field of BPD research.

英文关键词： lung development;newborn;genomice;DNA methylation;epigenetice