生命早期IGF-1通过MEK/ERK信号通路影响SGA追赶生长不良儿童认知功能的机制研究

Small for gestational age (SGA) could lead to many metabolic and neurodevelopmental diseases in later life. Our prior study found that there was a fairly large number of SGA children were unable to achieve the appropriate catch-up growth in the process of growth which lead to a higher risk of impaired cognitive function, while the detail mechanisms are still elusive. Insulin-like Growth factor-1 (IGF-1) was found to associated with catch-up growth and cognitive function in SGA by cross-sectional study. Our pilot study found that IGF-1 was decreased in cord blood of SGA newborn. In this project, with the aid of large prospective cohort study, 367 SGA and 367 healthy controls were recruited and followed. Cognitive function, physical growth were examined at the age of 5. This study aims to explore whether the cord blood IGF-1 level was associated with the growth outcomes and cognitive function of SGA children at the age of 5. In this case, early identification and intervention could be carried out for children who were unable to well catch up growth. This study further established the SGA rat model without catch-up growth, embedded micro-injection catheter into the lateral ventricle and given IGF-1 and IGF-1 receptor inhibitor to explored whether IGF-1 could improve the cognitive function of SGA rat without catch-up growth through Mitogen-activated protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) signaling pathway. The research results are expected to provide theoretical basis for early prediction and accurate intervention of impaired cognitive function in SGA.

小于胎龄儿(SGA)远期易发生多种代谢与神经发育健康问题。我们前期利用大型出生队列数据研究发现，部分SGA儿童出生后无法实现最佳追赶生长，易导致认知功能障碍。但目前机制仍不明确。横断面研究发现胰岛素样生长因子-1(IGF-1)与SGA追赶生长、认知功能均相关。本课题预实验发现，SGA脐带血中IGF-1降低。在此基础上：1.借助于大型前瞻性出生队列，纵向随访367名SGA及367名健康对照儿童，评估认知功能和生长发育，探讨生命早期IGF-1水平是否与SGA儿童期（5岁）的生长发育和认知功能相关，探索IGF-1是否可以用于早期识别追赶生长不良的SGA人群。2.建立SGA追赶生长不良大鼠模型，给予外源性IGF-1和IGF-1受体抑制剂,探索IGF-1是否通过MEK/ ERK信号通路改善SGA追赶生长不良群体的认知功能。研究成果有望为SGA认知功能受损的早期预测及精准干预提供理论依据。

小于胎龄儿(SGA)发病率居高不下，远期易伴发多种并发症。部分SGA儿童在生长过程中始终无法实现最佳追赶生长，易导致认知功能障碍。对这部分人群的识别及干预目前仍存在滞后现象。因此，本研究借助于前瞻性出生队列，收集SGA健康对照儿童的脐带血、胎盘组织以及6个月、1岁、2岁、4岁时的病史数据及血液样本，测定不同时点的生长发育水平，在12月、2岁、4岁时进行认知功能测定，探讨胰岛素样生长因子-1(IGF-1)水平与SGA儿童生长发育和认知功能结局的关系及可能机制，以期为减少SGA远期认知功能受损提供线索。结果发现：在导致SGA的危险因素中，母亲因素和胎儿因素均可增加儿童低智商风险。脐带血IGF-1水平与出生体重呈正相关，而与出生身长及6月、12月、24月体重及身长未发现相关关系。4岁IGF-1水平与出生身长、12个月及24月体重及身长均呈正相关。脐带血IGF-1与12个月ASQ总分、2岁bayley各分项分数及4岁韦氏结果均未发现相关关系。SGA儿童4岁IGF-1水平与2岁Bayley测试语言单项分呈负相关,与较高的动作单项分呈正相关。机制研究部分，本研究建立了SGA追赶生长不良大鼠模型，通过侧脑室置管给予外源性IGF-1和IGF-1受体抑制剂,探索IGF-1是否通过MEK/ ERK信号通路影响SGA追赶生长不良大鼠的认知功能，结果发现：1周龄及4周龄时，SGA组IGF-1水平均明显低于健康对照组。有追赶生长SGA组IGF-1水平高于无追赶生长SGA组，SGA各组子鼠海马组织中p-MEK1蛋白表达水平均低于健康对照组，SGA+IGF-1及SGA+IGF-1+PPP组与SGA-NC组相比，p-MEK1蛋白表达差异无统计学意义。结果表明不同致病因素导致的SGA儿童期结局不同，在生后管理时需区别对待。相对于脐带血IGF-1,儿童期IGF-1水平与生长发育及儿童期认知功能关系更加密切。