孕期蛋白质营养状况对生命早期1000天生长发育影响及相关胎盘氨基酸转运机制研究

The association between maternal protein status and the growth and development during the first 1000 days is always a hot puzzle, which has not yet been clarified，to date. It is urgent to comprehensively clarify the association between them, to figure out the corresponding key threshold and “window period” and to explore related mechanisms. The current project is a prospective study based on a large well-established birth cohort. We intend to assess maternal protein nutrition status comprehensively by monitoring the protein intake, plasma protein and free amino acid levels during early, middle and late pregnancy, respectively. Then, we will track the growth during the first 1000 days, and evaluate the infant development by Bayley Scales of Infant Development (BSID-Ⅱ). Further, we used spline smoothing based on a generalized additive model and the threshold effect analysis based on a two-piece-wise multiple linear regression model to assess the effect of maternal protein status on the growth and development during the first 1000 days and find out the corresponding key threshold value and "window period". Moreover, we will take IGF-1 and so on as the breakthrough points, to evaluate the effect of maternal protein status on the expression of amino acid transporters and to further explore the underlying mechanism between maternal protein status and fetal intrauterine growth. The implementation of this project can not only provide scientific basis for reasonably guiding protein nutrition in each pregnancy to ensure the health during the 1000 days, but also provide a new direction for preventing chronic diseases in adulthood and the lifelong health, which may be of great theoretical and application significance.

孕期蛋白质营养与“生命早期1000天”生长发育的关系一直备受关注，但至今远未阐明。全面揭示二者关系，明确相应关键阈值和“窗口期”并探索相关机制迫在眉睫。本项目拟在已有大型出生队列基础上运用前瞻性队列研究方法，全面监测孕妇早、中、晚各期蛋白质摄入、血浆蛋白质和游离氨基酸水平，综合评估蛋白质营养状况；追踪“生命早期1000天”体格生长情况并采用BSID-Ⅱ量表评估发育情况；运用基于GAM的曲线拟合方法和基于分段MLR模型的阈值效应方法，全面揭示各孕期不同蛋白质营养状况对该阶段生长发育的影响并提出相应关键阈值及“窗口期”；最后，以IGF1等为切入点，分析孕期蛋白质营养对胎盘氨基酸转运体表达水平影响进而探讨其影响宫内生长发育的机制。本项目的实施不仅可为合理指导各孕期蛋白质营养，保证“生命早期1000天”健康提供科学依据，还可为预防成年期慢性病、促进一生健康提供新的切入点，具有极大的理论和应用价值。

“生命早期 1000 天”是人一生中体格生长和大脑发育最快的阶段，更是决定新生命一生健康的“窗口期”。蛋白质作为一切生命的物质基础，与生长发育密切相关。孕期蛋白质营养与“生命早期1000天”生长发育的关系一直备受关注，但至今远未阐明。国内外现行的孕期蛋白质推荐摄入量并未考虑子代健康效应，尚不能有效指导孕期实践。全面阐明二者关系并明确其“窗口期”及关键阈值，探索相关机制迫在眉睫。本项目依托前期建立的大型出生队列，全面监测并综合评估了孕妇各孕期蛋白质营养状况并发现武汉市城市孕妇的蛋白质营养水平普遍较高。其中，中期蛋白质摄入平均值达到1.32g/kg，接近欧美同期水平。运用基于GAM的曲线拟合方法和基于分段MLR模型的阈值效应方法，从孕期血浆蛋白质指标和膳食蛋白质摄入两个层面分析均发现孕中期蛋白质营养与后代体格生长存在阈值效应，并成功提出相应“窗口期”及关键阈值。具体来讲，孕中期蛋白质摄入水平<1.01 g/kg/d时，后代2岁时身长随孕期蛋白质摄入水平升高而升高；当孕中期蛋白质摄入水平≥1.01 g/kg/d时，后代2岁时身长却随孕期蛋白质摄入水平升高而显著下降。但是2岁时体重和BMI则随母亲孕中期蛋白质摄入升高直线下降，提示孕期母亲膳食蛋白质摄入对后代横向生长和纵向生长的影响是不同的。.最后，以胎盘氨基酸转运体为切入点，分析孕期蛋白质营养对胎盘氨基酸转运体表达水平的影响，随着孕中期蛋白质摄入增加， SNAT4和LAT1呈现先上升后下降的趋势。这在一定程度上解释了孕期白质营养状况影响生命早期1000天体格生长的阈值效应的可能性。另以IGF-1、IGF1R、IGF-2、IGF2R等生长发育指标为切入点，发现IGF-1、IGF1R、IGF-2、IGF2RmRNA表达水平都随孕早期蛋白质营养水平的升高呈先上升后下降的趋势，也从一定程度上解释了孕期蛋白质营养影响胎儿宫内生长发育的机制的可能机制。本项目的实施不仅可为合理指导各孕期蛋白质营养以保证“生命早期1000天”健康提供科学依据，还可为预防成年期慢性病促进一生健康提供新的切入点，具有极大的理论和应用价值。