Mechanisms of Prostaglandin-induced Cervical Ripening in Humans

 描述(由申请人提供)：唯一最有效的早产预测指标是妊娠期间出现早产症状时的宫颈状况。足月生理性宫颈成熟的机制在很大程度上是未知的，早产宫颈扩张的原因更是难以捉摸。然而，众所周知，(I)外源性局部应用前列腺素可在妊娠的任何阶段诱导宫颈成熟，(Ii)PGH2 S的抑制剂(环氧合酶2，环氧合酶-2)能成功地阻止早产宫颈成熟。PGE2是宫颈中主要的COX2来源的前列腺素。因此，令人惊讶的是，宫颈中PGE2信号的下游靶点尚不清楚。通过初步研究，我们发现用于女性宫颈成熟的PGE2和前列腺素类似物(即地诺前列酮(PGE2)和米索前列醇(PGE1))通过复杂的基质细胞特异性机制抑制15-PGDH基因的表达。重要的是，PGE2通过EP2受体介导15-PGDH的下调，EP2受体在人宫颈间质细胞中高表达。这些发现使我们提出了一种假设，即PGE2-EP2相互作用在调节宫颈基质细胞在宫颈成熟过程中的转录程序中发挥重要作用。因此，这项提议的目的是：(I)探索全球 PGE2介导的基因在人宫颈基质细胞中表达的影响，(Ii)确定EP2受体激活导致宫颈基质细胞MITF-Cx和15-PGDH基因表达缺失的细胞信号转导机制，以及(Iv)确定EP受体拮抗剂是否在体内调节早产宫颈成熟。

 DESCRIPTION (provided by applicant): The single most effective predictor of preterm birth is the state of cervix during pregnancy upon presentation with symptoms of preterm labor. The mechanisms underlying physiological cervical ripening at term are largely unknown, and the causes of preterm cervical dilation are even more elusive. It is well-established, however, that (i exogenous topically-applied prostaglandins induce cervical ripening at any stage of pregnancy, and (ii) inhibitors of PGH2S (cyclooxygenase 2, COX-2) are successful in blocking preterm cervical ripening. PGE2 is the major COX2-derived prostanoid in the cervix. It is surprising, therefore, that the downstream targets of PGE2 signaling in the cervix are not known. By way of preliminary studies, we found that PGE2 and prostaglandin analogs commonly used for cervical ripening in women (i.e., Dinoprostone (PGE2) and Misoprostol (PGE1)) suppress 15-PGDH gene expression through complex stromal cell-specific mechanisms. Importantly, PGE2-induced down regulation of 15- PGDH was mediated through EP2 receptors, highly expressed in human cervical stromal cells. These findings led us to propose the hypothesis that PGE2-EP2 interactions play important roles in regulating the transcriptional program of cervical stromal cells during cervical ripening. The aims of this proposal, therefore, are to (i) explore the global effects of PGE2-mediated gene expression in human cervical stromal cells, (ii) define the cellular signal transduction mechanisms by which activation of EP2 receptors leads to loss of MiTF-CX and 15-PGDH gene expression in cervical stromal cells, and (iv) determine if EP receptor antagonists regulate preterm cervical ripening in vivo.