褪黑素激活Nodal/TGF-β信号通路在围孕期睡眠影响子代心脏发育中的作用机制研究

Our previous case-control study found that sleep during pregnancy was associated with congenital heart disease (CHD) in offsprings. Based on the finding, a prospective cohort study is specifically designed to observe sleep parameters across multiple dimensions before and in the first trimester of pregnancy, and then to examine the longitudinal associations of sleep and its trend with the incidence of CHD. Furthermore, the biological mechanisms underlying the associations would be explored and interpreted: ① how sleep during pregnancy affects the secretion and expression of melatonin; ② if melatonin mediates the activation of “Nodal-Smads-Pitx2” signaling pathway; and, particularly, ③ how melatonin promotes the differentiation of embryonic stem cell to heart specific progenitor cell, and how melatonin governs the heart morphogenesis. Based on all the above, the relationship mathematical model regarding melatonin linking maternal sleep and offspring CHD would be established. In summary, this study aim to systematically examine the role of sleep during peri-conception period in the embryonic heart development, which would foster new progress in the etiology of CHD, meanwhile, would promote the understanding of health effect of sleep during pregnancy on the development of offspring. All the evidence would be significant to enrich perinatal and prenatal health care knowledge which can be used in clinical practices in order to enhance aristogenesis and stirpiculture.

本课题组前期病例-对照研究提示孕妇睡眠与子代先天性心脏病（Congenital heart disease,CHD）发病相关。基于此发现，本项目于孕前、孕早期多维度评估睡眠参数，前瞻性评估睡眠参数及孕前→孕早期参数变化与CHD发生之间的关联模式。以褪黑素为内暴露，观察睡眠对褪黑素分泌和表达的影响，以“Nodal-Smads-Pitx2”信号路径为生物机制效应指标，建立褪黑素作用于该信号系统的机制模型；结合人胚胎干细胞心肌分化模型，阐述褪黑素参与胚胎心脏细胞分化及形态结构形成的分子机制。综合上述，以褪黑素激活Nodal信号系统为切入点，构建暴露-机制-效应之间的数学模型，论述母亲孕期睡眠参与子代心脏发育调控的生理基础。研究首次比较系统阐述孕期睡眠影响胚胎心脏发育的生物学效应及分子机制，有望在CHD的病因学和孕期睡眠健康效应论述上取得新进展，对于丰富孕期保健理论知识和促进优生优育意义重要。

本项目于孕前、孕早期多维度评估睡眠参数，前瞻性评估睡眠参数及孕前→孕早期参数变化与先天性心脏病（congenital heart disease, CHD）发生之间的关联模式。以褪黑素为内暴露，阐述睡眠参与胚胎心脏细胞分化及形态结构形成的分子机制。.研究取得如下成果：.一.分别于孕早、中、晚期纵向评估了单胎和双胎孕期孕期睡眠的多个参数，首次获得了中国人孕期睡眠特征的前瞻性流行病学资料。其中，有关双胎孕妇睡眠特征的数据有望填补国际研究空白。.二.基于病例对照研究平台和孕期睡眠专项队列，回顾性、前瞻性分析孕期睡眠暴露和子代CHD的关系，首次提供了孕期睡眠与子代CHD发病相关的人群流行病学证据。.三.白天小睡时可使由睡眠问题导致的简单CHD发病风险降低29.6%，在倾向性评分校正分析中，这种关联仍然存在；该发现对于研究孕妇睡眠健康促进具有启发价值。.四.体外细胞实验观察到孕妇睡眠问题可通过褪黑素介导干扰胚胎心脏发育调控，PI3K-AKT信号通路可能参与其中，使细胞周期在G1至S期发生阻滞。此外，妊娠睡眠问题可导致皮质醇信号通路关键基因甲基化修饰发生改变，提示孕期睡眠的健康效应有可能通过表观遗传机制而具有潜在跨代遗传影响的风险。.本研究初步确立了围孕期睡眠与子代CHD发病之间的相关性，首次从人群流行病学的角度论述了母亲睡眠在胎儿心脏发育调控中发挥重要作用；并以褪黑素为内暴露，比较系统阐述了多维度睡眠参与胚胎心脏发育调控的生理学机制，研究结果对于丰富孕期保健理论知识和促进优生优育意义重要。