胆固醇代谢基因ABCA1参与早产发病的相关途径研究

Preterm birth (PTB) is the leading cause of prenatal mortality. The mechanisms for PTB are still unclear. Among common identified pathways for PTB, there are intrauterine infections and elective prematurity. But most cases appear no risk factors. Relative studies show dyslipidemia resulting from ABCA1 gene variation is associated with spontaneous preterm birth. Our previous researches exhibited the significant interactions between -477C/T genotypes in promoter region of ATP Binding Cassette Transporter (ABCA1) Gene and PTB. These discovers have led to the hypothesis that common variation in the ABCA1 gene could affect the placental ABCA1 expression, interfere the trophoblastic lipid metabolism and macrophages secretion of inflammation cytokines, which result in activation of PTB. In order to prove our thesis, we will firstly explore the placental morphological characteristics in preterm labor by immunohistochemisty, immunoblotting and RT-PCR. Secondly we will investigate the changes of trophoblastic subcellular structure by laser confocal fluorescence microscope and variation of cholesterol level by luciferase activity. Finally, we will analyze the role of ABCA1 protein in regulation of inflammation cytokine by tissue chip immunohistochemistry. Our study is of great significance on illustration the mechanism of ABCA1 gene variation in PTB.

早产是围产儿死亡的首要原因,除了宫内感染等常见病因外，约50%早产的发病机制不清楚。我们前期研究显示，胆固醇代谢基因ABCA1多态性与早产孕妇外周血及脐带血血脂水平相关，早产胎盘ABCA1基因mRNA和蛋白表达水平上调。ABCA1基因表达改变是否诱发早产以及通过何种途径诱发早产,尚无文献报道，我们推测可能的途径为: 母胎界面ABCA1基因表达改变,①使滋养细胞脂质代谢异常,导致滋养细胞损伤;②使胎盘巨噬细胞免疫调控发生异常,炎性细胞因子分泌失衡，从而诱发早产。为了证实上述设想，本研究通过建立早产胎盘滋养细胞和巨噬细胞实验模型,分别从组织学、细胞学和分子水平,探讨早产胎盘组织脂代谢的形态学特点；探讨ABCA1基因表达改变对滋养细胞和巨噬细胞超微结构的影响、对滋养细胞胆固醇代谢及巨噬细胞免疫调控功能的影响。希望通过本研究为阐明ABCA1基因参与早产发病的具体途径，揭示早产的发病机制提供新视角。

早产（Preterm delivery, PTD）是妊娠期常见并发症，是围产儿死亡的首要原因。目前认为宫内感染等因素可诱导早产的发生，但仍然有约50%的早产发病机制不清楚。有研究报道胆固醇代谢基因ABCA1的异常表达与早产的发生发展关系密切，但是关于在早产发生及其发展的过程中ABCA1 所起到的作用及作用机制尚不清楚。本研究的目的为通过研究ABCA1 在早产孕妇胎盘组织中表达情况，探讨ABCA1 在早产发病过程中的作用，并初步阐明其作用机制。我们研究发现，自发性早产孕妇胎盘中ABCA1 的表达水平高于医源性早产孕妇以及足月产孕妇，而医源性早产孕妇胎盘中ABCA1 的表达水平与足月产孕妇胎盘中ABCA1的表达水平之间无明差异。胎盘组织中ABCA1 表达升高，可使得胎盘滋养细胞胆固醇转运功能出现异常，导致母胎界面胆固醇代谢出现紊乱；同时，ABCA1可导致滋养细胞的趋化因子表达水平出现异常以及胎盘巨噬细胞分泌炎性因子的水平发生改变，使得母胎界面的免疫调控出现异常，从而诱导早产的发生。本研究可为揭示早产的发病机制提供新的思路和视角，对于降低早产的发病率，提高出生人口素质，开展成人代谢病的宫内极早期预防具有重要的意义。