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

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.

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

项目研究背景：宫内生长迟缓（IUGR）的个体在成年后有发生肺动脉高压或者对低氧有高度敏感性的风险，这种表型是否受到表观遗传调控。研究方向： 探讨 IUGR 可能诱导与肺高压相关基因的表观遗传修饰及与人体相对应的IUGR脐静脉内皮细胞相关的分子水平改变以及表观修饰，探索生后早期的营养措施是否可以降低 IUGR 成年后发生肺高压风险。主要内容：分为四个部分：对IUGR脐静脉内皮细胞失调及其相关分子学水平的调控机制2) 对于IUGR子代生后早期营养干预与肺高压关系的研究，3) 对于 IUGR 外周白细胞改变与哮喘的表观调控机制的研究，4) 对于 IUGR 平滑肌细胞调控肺动脉高压的表观遗传机制的研究。重要结果：IUGR 促进血管内皮细胞增殖，其调节血管张力、调节氧化应激、调节血管生成的相关表达水平都有明显改变。而在生后继续控制进食可以在一定程度上降低其在成年期发生肺血管功能失调的风险，表观遗传修饰的改变可能参与其中。IUGR 大鼠外周血白细胞的表观遗传改变或许可以作为疾病发生风险的生物标记物。缺氧引起 IUGR 大鼠原代肺动脉平滑肌细胞增殖效应与 Kv1.5 通道蛋白酪氨酸磷酸化位点的激活有关。关键数据：共培养博士研究生7名，硕士研究生3名。科研成果已总结撰文，以标注发表形式发表SCI 收录论文6篇，其中1篇综述。主译著作1篇。 科学意义：本研究对解释胎儿来源的成人疾病的表观遗传机制以及早期恰当的干预能够降低生命后期发生肺动脉高压的风险具有重要意义，为新生儿期的肺动脉高压以及后期的肺动脉高压治疗提供新的思路，并为胎儿来源的成人疾病提供新的理论依据。