新生儿死亡的首要原因是早产，研究早产发生机制寻找防治早产有效手段不仅可以降低新生儿死亡率而且还可以从源头上防止早产相关新生儿重大疾病的发生。前列腺素收缩子宫、成熟宫颈和促胎膜破裂，是公认的启动分娩的最后通路。胎膜既是前列腺素也是皮质醇的重要来源，申请人前期工作发现，胎膜大量表达皮质醇再生酶11β-HSD1，皮质醇与促炎性细胞因子协同诱导胎膜11β-HSD1表达，由此产生的皮质醇通过诱导前列腺素合成酶cPLA2和COX-2促进前列腺素的合成，从而在胎膜形成以11β-HSD1为核心、以前列腺素合成为靶向的正反馈环路。我们认为11β-HSD1的高表达和此正反馈环路的过早过度激活可能是早产的重要原因，本课题拟利用临床样本研究11β-HSD1与分娩启动和早产之间的关系、研究11β-HSD1基因多态性与原发性早产的关系、利用恒河猴动物实验研究11β-HSD1抑制剂防治早产的可能性。

Preterm birth is the leading cause of neonatal death. Elucidation of the mechanisms underlying preterm birth will provide means to reduce not only neonatal mortality but also the morbidity of life-threatening diseases related to preterm birth. Prostaglandins are the final common pathway of parturition initiation via promoting myometrial contraction, cervical ripenning and membrane rupture. Fetal membranes are not only the major sources of prostaglandins but also the important sources of cortisol in pregnancy. We have provided convincing evidence that the fetal membranes express abundant 11β-HSD1 which regerates cortisol from cortisone and cortisol has positive feedback on 11β-HSD1 expression in the fetal membranes, which is potentiated by pro-inflammatory cytokines. Cortisol derived from 11β-HSD1 increases prostaglandin production via indution of the key prostaglandin synthesizing enzymes (cPLA2 and COX2), thus forming a feedforward loop of cortisol regeration and subsequent prostaglandin production in the fetal membranes. We hypothesize that early and over-activation of 11β-HSD1 expression might lead to preterm birth. Here we propose a translational study of the relationship between 11β-HSD1 and parturion as well as preterm birth and the relationship beween SNPs of 11β-HSD1 gene and idiopathic preterm birth by using human fetal membranes collected from term pregnancy with and without labor as well as from preterm birth. We will also to explore the possibility of clinical use of specific inhibitor of 11β-HSD1 to prevent preterm birth by using a rhysus monkey model.