孕期过多糖皮质激素暴露被认为是“印迹”胎源性成年疾病主要因素之一，我们证实孕期皮质激素过量可致子代宫内发育迟缓和成年期代谢综合征（肥胖、血脂紊乱、高血糖等）。胎盘II型11β-羟基类固醇脱氢酶（11β-HSD2）将母体活性糖皮质激素代谢成无活性的皮质酮而担负糖皮质激素屏障作用。前期研究显示胎盘Sonic hedgehog（Shh）信号通路活化不仅促进胎盘合体化过程，还可促进胎盘11β-HSD2表达。然而Shh信号通路调控11β-HSD2的具体效应和机制尚不明确。本项目拟在前期研究基础上，采用细胞培养、慢病毒介导RNA干扰和胚胎移植等技术，探索胎盘11β-HSD2表达调控机制的基础上，探索胎盘特异Shh基因敲降对胎盘和胚胎发育的影响及可能机制，并进一步利用孕期胎盘Shh基因敲降的成年鼠探索代谢综合征易感性及可能分子机制。这将为临床代谢综合征发生提供新的理论依据及可能的预警策略。

Excessive glucocorticoid exposure during pregnancy is considered to be a main factor to "imprinted" the fetal origin of adult disease (FOAD). Our studies confirmed that excessive glucocorticoid exposure during pregnancy induced intrauterine growth retardation (IUGR) and adulthood metabolic syndrome (e.g. obesity, dyslipidemia, and hyperglycemia) of their offsprings. Placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is regarded as a glucocorticoid barrier as it devitalize the active glucocorticoids from their parent into inactive cortex ketone. Our previous study showed that activiation of placental Sonic hedgehog (Shh) signal pathway not noly promoted the process of trophoblast cells fusion by down-regulating the expression of ZO-1 and increasing the production of β-hCG, but also up-regulated the expression of placental 11β-HSD2. However, the acurate effect and mechanisim of Shh signal pathway on the regulation of 11β-HSD2 is still unclear. In this study, we used the cell culture, lentivirus-mediated RNA interference and embryo transfer technology to investigate the placental 11β-HSD2 expression and regulation mechanism (have established a pregnant mice model with placenta-specific Shh gene knockdown), analyze the effect of placenta-specific Shh gene knockdown on placental and embryonic development and its possible mechanism. Moreover, we use the placenta Shh gene knockdown adult rats to explore the susceptibility to metabolic syndrome and its possible molecular mechanism. This will provide a new possible theoretical basis and early warning strategy of clinical metabolic syndrome.