先天性心脏病（CHD）居出生缺陷首位，其发生与毒物及药物暴露密切相关。上调胎盘P-糖蛋白（P-gp）可减少致畸物进入胎儿侧，降低胎儿CHD发生率。申请者前期证实维生素D受体（VDR）可在转录水平上调胎盘P-gp表达。鉴于VDR广泛的生物学作用及VDR配体常导致高钙血症等副作用的发生，亟需探寻更为特异上调胎盘P-gp的干预靶点。VDR必须募集辅激活因子（DRIP复合物或SRC家族）才能启动基因转录，DRIP复合物及SRC家族的亚基/亚型构成、分布特征及表达水平在VDR介导基因时空特异性表达调控中起关键作用。本项目拟揭示VDR介导胎盘P-gp转录调控中特定的DRIP及SRC募集方式和分布特征，阐明VDR-DRIP/SRC复合物对胎盘P-gp的调控机制,探寻降低药物及毒物胎盘转运率的特异性干预靶点，减少药物及毒物对心脏发育的不利影响，前移CHD“防控阵线”，从胎盘视角探索CHD一级预防新思路。

Congenital heart defect (CHD) is the most common birth defects. The origins of CHD are closely related to toxicants and drugs exposure. Placental P-glycoprotein (P-gp) elevation could significantly decrease the transplacental transfer rates of toxicants and drugs, and thereby reduce their adverse effects on cardiac development. Our previous study proved that placental P-gp could be regulated by vitamin D receptor (VDR) transcriptionally. Due to the extensive biological influence of VDR and various side effects of its ligands, more specific targets involving P-gp up-regulation are extremely warranted. Coactivators including the DRIP complex and SRC family, are necessary in the process of VDR mediated gene transcription. The subunit of DRIP, subtype of SRC, their distribution and expression level play a key role in determining the gene tissue specific expression. This study aims to reveal the specific recruitment and distribution characteristics of DRIP complex and SRC family in the process of VDR mediated P-gp transcriptional regulation, and elucidates the regulation mechanism of P-gp regulation by VDR-DRIP/SRC complex, seeking the specific targets for reducing the transplacental transfer rates of toxicants and drugs and its adverse effects on cardiac development, and subsequently forwarding CHD prevention front, which might provide a brand-new insight for primary prevention of CHD in the profile of placenta.