INHIBITION OF UTERINE CONTRACTIONS BY FETAL MEMBRANES

这项提案的目的是研究人类胎膜的作用 抑制系统在控制子宫收缩与长 术语目标是理解启动过程中涉及的基本机制 劳动。维持子宫静止的生物学机制 在怀孕的大部分时间里， 没有被清楚地理解。胎膜，羊膜和绒毛膜， 母体蜕膜被认为在旁分泌信号传导中是重要的 以及控制子宫收缩、宫颈扩张和分娩。的 胎膜介于胎儿和母体蜕膜之间， 子宫肌因此，它们是调节信号的理想位置 在分娩开始时母亲和胎儿之间的关系。过去的研究 许多研究者的努力集中在子宫刺激器上， 从胎膜释放的收缩。最近，我们开发了一个双 室-胎膜-子宫肌体外模型，以研究 胎膜、母体蜕膜和子宫肌肉的相互作用。在 在这个系统中，胎膜被密封在一个有机玻璃腔中， 每个半室是胎儿侧或母体侧的隔室。 在母体一侧增加子宫肌条。因此， 子宫上的胎膜可以通过测量 子宫收缩的变化。系统的所有组件，胎儿 膜、母体侧信号和子宫肌肉模型可以 很容易在体外系统中操作。在最近出版的作品中，我们 出乎意料地发现，人类足月分娩的胎膜抑制 自发性子宫收缩，这种抑制是可逆的， 抑制作用是特异性的绒毛膜/蜕膜侧 因为羊膜侧朝向肌肉的膜 显示抑制。这改变了我们研究工作的重点， 对存在于胎膜中的抑制系统的刺激。 此外，本提案中显示的初步数据表明， 胎膜因子能够抑制BAY K8644（一种L-型钙离子通道， 通道激动剂）诱导子宫收缩。这些数据导致 提出了一个假设，即胎儿膜抑制剂是内源性的， 钙通道拮抗剂胎儿膜抑制物质具有 潜在的重要监管机构在启动劳动以及 作为治疗分娩启动的新疗法的潜力 异常，如早产。这一修订后的第一批赠款申请 提出了一系列的实验，以分配的作用机制， 作为内源性钙通道抑制剂的胎膜因子，和 确定胎膜抑制物对胎儿发育的重要性 劳动

The purpose of this proposal is to study the role of human fetal membrane inhibitory systems in the control of uterine contractions with the long term goal of understanding the basic mechanisms involved in the initiation of labor. The biological mechanisms that maintain uterine quiicscence throughout most of pregnancy and cause the transition to labor at term are not clearly understood. The fetal membranes, the amjiion and chorion, and the maternal decidua are thought to be important in paracrine signalling and control of uterine contractions, cervical dilation and birth. The fetal membranes are interposed between the fetus and maternal decidua and uterine muscle. Thus, they are ideally positioned to regulate signal1ing between mother and fetus at the time of initiation of labor. Past research efforts by many investigators focused on stimulators of uterine contractions released from fetal membranes. Recently, we developed a dual chamber-fetal membrane-uterine muscle in vitro model to study the interactions of fetal membranes, maternal decidua and uterine muscle. In this system, fetal membranes are sealed into a Plexiglass chamber so that each hemichamber is a compartment for either the fetal or maternal side. A uterine muscle strip is added to the maternal side. Thus, effects of fetal membranes on the uterus can be assessed directly by measuring changes in uterine contractions. All components of the system, fetal membranes, maternal side signals and the uterine muscle model can be easily manipulated in this in vitro system. In recently published work, we unexpectedly found that human, term, labored fetal membranes inhibit spontaneous uterine contractions, that this inhibition is reversible and that the inhibitory effect is specific to the chorion/decidual side because membranes mounted with the amnion side toward the muscle did not show inhibition. This has changed the focus of our research efforts from stimulatory to inhibitory systems which are present in fetal membranes. Furthermore, preliminary data shown in this proposal suggests that the fetal membrane factor is able to inhibit BAY K8644 (a L-type calcium channel agonist) induced uterine contractions. These data lead to the proposed hypothesis that the fetal membrane inhibitor is an endogenous calcium channel antagonist. Fetal membrane inhibitory substances have potential as important regulators in the initiation of labor as well as potential as new therapies in the treatment of labor initiation abnormalities such as preterm labor. This revised FIRST grant application proposes a series of experiments to assign a mechanism of action for the fetal membrane factor as an endogenous calcium channel inhibitor, and establish the significance of the fetal membrane inhibitor to the onset of labor.