Regulation of Prostaglandin Endoperoxide Synthase-2 in the Human Fetal Membranes at Birth

早产导致婴儿不成熟是新生儿死亡和患病的主要原因。早产发生在6%至11%的怀孕中，其比率在工业化国家正在缓慢增加。我们需要更好地了解分娩过程的调节，以找到扭转这一趋势的方法。前列腺素是一种激素物质，刺激子宫收缩、宫颈扩张和胎膜破裂。子宫内组织产生前列腺素，子宫内前列腺素水平的增加可能是导致正常分娩和早产的原因。我们先前已经在胎膜中鉴定出一种酶蛋白，称为前列腺素合酶-2，其在妊娠期间子宫内前列腺素的合成中具有关键作用。这种酶在分娩开始前表达越来越多。在本申请中，我们提出研究以确定是什么导致表达增加。我们推测，编码这种酶的基因是专门在胎膜中激活，为分娩做准备。我们将通过测定自然分娩或足月和早产不分娩的妇女组织中基因的活性来确定调控机制。此外，我们将确定在这些怀孕的前列腺素合酶-2基因的调节蛋白的相互作用，以了解在分子水平上的调节机制。最后，我们将进行细胞培养研究，以实验方式操纵前列腺素合酶-2基因在胎膜细胞中的活性。作为这项工作的总体成果，新的目标可能会被确定为药物破坏前列腺素合酶-2基因激活，特别是在胎膜。长期的观点是阻断子宫内前列腺素的合成，以抑制早产和预防早产。

Preterm birth with the resulting immaturity of babies is the leading cause of death and disease among newborns. Early birth occurs in 6 to 11% of pregnancies, and its rate is slowly increasing in industrialized countries. We need a much better knowledge of the regulation of the parturition process to find ways to reverse this trend. Prostaglandins are hormonal substances that stimulate uterine contractions, cervical dilatation and membrane rupture. Intrauterine tissues produce prostaglandins, and an increase of prostaglandin levels in the uterus is likely responsible for inducing labour both normally and preterm. We have previously identified an enzyme protein in the fetal membranes, called prostaglandin synthase-2, that has a key role in the synthesis of intrauterine prostaglandins during pregnancy. This enzyme is increasingly expressed before labour onset. In the present application, we propose studies to determine what causes the increased expression. We hypothesize that the gene encoding this enzyme is specifically activated in the fetal membranes in preparation for labour. We will define the mechanism of regulation by determining the activity of the gene in tissues from women who deliver either spontaneously or without labour at term and preterm. Further, we will determine the interaction of regulatory proteins with the prostaglandin synthase-2 gene in these pregnancies in order to understand the mechanisms of regulation at the molecular level. Finally, we will conduct cell culture studies to experimentally manipulate prostaglandin synthase-2 gene activity in fetal membrane cells. As an overall outcome of this work, new targets may be identified for drugs to disrupt prostaglandin synthase-2 gene activation specifically in the fetal membranes. The long term perspective is to block prostaglandin synthesis in the uterus in order to suppress preterm labour and prevent preterm birth.