围产期营养因素对早产儿肺血管发育的调控机制及干预策略

Adverse environment in early life, including intrauterine growth retardation (IUGR) and extrauterine growth retardation (EUGR) is closely related to the development of pulmonary hypertension later in life. Epigenetic regulation plays an important role in this phenomenon of fetal origin of adult diseases, which can be inherited to the next generation. Our previous studies have found that unlike other transgenerational effects, female offspring following EUGR male parents showed a significant reduction in pulmonary artery pressure later in life compared with those sex-matched control group. In view of this different transgenerational effect, we hypothesize that IUGR and EUGR could cause similar somatic epigenetic changes of pulmonary hypertension-related genes, but could produce different epigenetic changes in the germ cells. Furthermore, early appropriate interventions might reverse epigenetic modifications of pulmonary hypertension-related genes, and passed through the sperm cells. The interventions might have a protective effect on the development of pulmonary hypertension later in life and even in progeny. RNA modifications may be involved in this mechanism. Based on those, the present study will examine different epigenetic changes of pulmonary hypertension-related genes from somatic and germ cells. The plan would explain the mechanisms of the “fetal origin of adult diseases” theory and transgenerational effects, providing a new insight into preventing and controlling the fetal origin of adult diseases.

生命早期不良环境包括宫内生长迟缓（IUGR）和宫外生长迟缓（EUGR）与成年期肺动脉高压的发生密切相关，表观遗传调控起重要作用，这种胎儿来源的成人疾病现象可以遗传至下一代。课题组先前研究发现与其它世代遗传不同，EUGR雄性父代的雌性子代在成年期的肺动脉压力较同性别对照组子代显著降低。本课题针对这种不同的世代遗传现象，提出IUGR和EUGR虽可以引起体细胞肺高压相关基因相似的表观遗传改变，但对生殖细胞可能产生不同的表观修饰改变的假设。而且生命早期的适当干预措施能够逆转相关基因的表观修饰，并可通过精子细胞进行传递，对生命后期以及子代肺血管不良效应可能有保护作用，而RNA修饰可能涉及到该机制。基于此，本课题利用表观遗传方法研究肺高压相关基因在体细胞和生殖细胞不同的表观修饰变化，这将对解释胎儿来源的成人疾病的表观遗传以及世代遗传机制具有重要意义，为胎儿来源的成人疾病的控制提供了一个新的思路。

生命早期不良环境与成年期肺动脉高压的发生密切相关，表观遗传调控起重要作用,这种胎儿来源的成人疾病现象可以遗传至下一代。本课题建立宫、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）和肺动脉平滑肌细胞（PASMC）功能失调，肺动脉高压(PAH)发生率增加。甲基化RNA免疫沉淀测序结果显示肺发育相关蛋白表达改变，ChIP、DNA 甲基化的技术结果显示肺血管内皮功能失调可通过精子的表观修饰遗传至子二代。生命早期的适当营养干预措施能够逆转相关基因的表观修饰，对生命后期的肺血管不良效应有保护作用。本研究对解释胎儿来源的成人疾病的表观遗传以及世代遗传机制具有重要意义，为围产期营养干预提供了一个新的思路。