Function of the Decidual Tissue

描述（由申请人提供）：妊娠的建立和维持需要专门的母体组织--蜕膜的协调活动。我们和其他实验室的广泛研究已经确定，蜕膜细胞能够产生激素和细胞因子，并表达类固醇生成酶。我们研究的总体目标是了解这些蜕膜衍生因子在维持胎儿发育的适当环境中的作用。基因敲除策略已经揭示了催乳素（PRL）、白细胞介素-11（IL-11）和蜕膜类固醇生成酶、1型5 α-还原酶（5alphaR 1）和20 α-羟基类固醇脱氢酶（20 alphaHSD）在啮齿动物妊娠的正常进展中的关键作用。本基金申请的重点是确定这些蜕膜衍生因子的作用、调节和相互作用。第一个具体目标集中在蜕膜PRL在抑制IL-6和caspase-3中的作用，IL-6和caspase-3分别参与炎症和细胞死亡。使用PRL和IL-6基因敲除以及原代蜕膜细胞和细胞系，我们建议检查是否确实是IL-6表达导致PRL（-/-）小鼠中的胎儿死亡，是否可以通过产生PRL和IL-6的双敲除小鼠以及通过防止PRL缺失小鼠中的IL-6产生来挽救妊娠。我们还将确定PRL沉默IL-6基因的蜕膜表达的分子机制。这一特定目标的另一个目的是基于我们的发现，即dPRL作为一种生存因子，阻止细胞死亡诱导剂caspase-3在蜕膜中的表达和激活。我们将研究dPRL阻止这个刽子手caspase的活性的机制，并确定PRL抑制caspase 3是否在转录水平上，并涉及Akt/forkhead通路。第二个目标将集中在蜕膜IL-11在正常妊娠过程中的作用，更具体地说，IL-11 R α基因缺失导致小蜕膜和不受控制的滋养层浸润的原因。最后，在第三个目标中，我们将研究蜕膜类固醇生成酶在维持妊娠中的调节和作用。我们将研究PRL阻止蜕膜20 α HSD表达的机制，以及PGF 2a是否在妊娠结束时刺激其表达。我们还将检查是否在IL-11 R α缺失小鼠中不表达5 α R1，导致高水平的循环雌二醇和促胎儿死亡。我们还将检验以下假设：5 α还原酶1型缺失小鼠的胎儿死亡是由于高水平雌二醇抑制了蜕膜中的IL-11信号传导。

DESCRIPTION (provided by applicant): The establishment and maintenance of pregnancy requires the coordinate activity of a specialized maternal tissue, the decidua. Extensive investigation from our and other laboratories has established that decidual cells are able to produce hormones and cytokines, and to express steroidogenic enzymes. The overall objective of our research is to understand the involvement of these decidua-derived factors in the maintenance of the proper milieu for fetal development. Gene knockout strategies have revealed a crucial role for prolactin (PRL), Interleukin-11 (IL-11) and for decidual steroidogenic enzymes, 5alpha-reductase type 1 (5alphaR1) and 20a-hydroxysteroid dehydrogenase (20alphaHSD), in the normal progress of pregnancy in rodents. The focus of this grant application is to define the role, regulation and interaction of these decidua-derived factors. The first specific aim centers on the role of decidual-PRL in the inhibition of IL-6 and caspase-3, genes involved in inflammation and cell death respectively. Using both PRL and IL-6 knockouts as well as primary decidual cells and cell lines, we propose to examine whether it is indeed IL-6 expression that leads to fetal death in the PRL (-/-) mice, whether pregnancy can be salvaged by generating double knockout mice for PRL and IL-6, and by preventing IL-6 production in the PRL null mice. We will also determine the molecular mechanism by which PRL silences the decidual expression of the IL-6 gene. Another objective of this specific aim is based on our findings that dPRL acts as a survival factor preventing the expression and activation of the cell death inducer, caspase-3, in the decidua. We will examine the mechanism by which dPRL prevents the activity of this executioner caspase, and determine whether PRL inhibition of caspase 3 is at the transcriptional level and involves the Akt/forkhead pathway. The second aim will focus on the role of decidual IL-11 in the normal progress of pregnancy and more specifically on the reason why IL-11Ralpha gene deletion leads to small decidua and to uncontrolled trophoblast invasion. Finally, in the third aim, we will examine the regulation and the role of decidual steroidogenic enzymes in the maintenance of pregnancy. We will examine the mechanism by which PRL prevents decidual 20alphaHSD expression and whether PGF2a stimulates its expression at the end of pregnancy. We will also examine whether 5alphaR1 is not expressed in the IL-11Ralpha null mice causing high levels of circulating estradiol and precipitating fetal death. We will also test the hypothesis that fetal death in 5alphaReductase type 1 null mice is due to the inhibition of IL-11 signaling in the decidua by high levels of estradiol.