生命早期营养与肺血管内皮细胞功能的表观调控机制研究

项目名称： 生命早期营养与肺血管内皮细胞功能的表观调控机制研究

项目编号： No.81471480

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杜立中

作者单位： 浙江大学

项目金额： 60万元

中文摘要： 生命早期是生长发育的关键时期，可塑性强。 研究及流行病学调查显示该阶段的营养不良与成年期心肺疾病相关。结合前期发现：新生儿肺动脉高压存在的表观遗传调控,提出从内皮细胞水平研究生命早期营养不良可诱导与肺高压相关基因发生表观遗传修饰改变，增加成年期肺血管疾病及肺高压的易感性的假说。建立宫、内外饮食受限所致的营养不良动物模型，发现其在成年期肺血管内皮细胞（PVEC）功能失调，肺动脉高压(PAH)发生率增加，PVEC中与肺血管相关的基因表达量改变。利用DNA甲基化基因芯片筛查出与肺高压相关的基因，使用Sequenom特定DNA片段甲基化检测及染色质免疫沉淀技术，体内、体外实验验证已知的基因表观修饰变化，及与成年期发生肺动脉高压或对低氧反应特性之间的关联性的分子机制；同时探讨早期营养干预措施对降低其相关的肺高压发生的保护作用。本研究对解释胎儿来源的成人疾病的表观遗传机制，及其早期干预能降低PAH风险

中文关键词： 表观遗传；营养；宫内/外生长迟缓；肺动脉高压；肺血管内皮细胞

英文摘要： Peritnatal life is considered as a critical time window for determination of long-term metabolic states and organ functions. However, the effects of nutritional disadvantages during peritnatal period on pulmonary vascular consequences in later life are not fully understood. Epigenetics plays an important role in the fetal origins of adult disease. Moreover, Endothelial dysfunction is regarded as a precursor of pulmonary arterial hypertension(PAH) and is also related to infant growth. We hypothesized that intrauterine growth retardation (IUGR) or extrauterine growth retardation (EUGR) could cause epigenetic modification of the genes that are related to lung development and pulmonary vascular tone regulation in later life, and early intervention could reduce the risk of IUGR/EUGR-related PAH later in life. We also hypothesized that there is an association between infant growth and endothelial function. In the present study, we will investigate the role of epigenetic regulation in IUGR/EUGR-related PAH in adulthood, and further investigate whether the appropriate interventions in the early stage of IUGR/EUGR individuals might decrease the risk of PAH in later life. The present study would elucidate the epigenetic mechanisms of the fetal origins of adult disease, and reveal the phenomenon that the early appropriate intervention could reduce the risk of PAH in later life. The study would provide new insights in the prevention and treatment of PAH in childhood or adulthood, and provide a new theoretical basis for controlling the fetal origins of adult disease, which could have an important clinical significance.

英文关键词： epigenetics;nutrition;intra-/extra-uterine growth restriction;pulmonary arterial hypertension;pulmonary vascular endothelial cell