Role of the Fetus in the Initiation of Parturition

描述(申请人提供)：我们假设，在女性和其他哺乳动物物种中，子宫静止是通过孕激素受体(PR)转录活性的增加来维持的，自发分娩是由一系列协同的生化事件启动或促进的，这些生化事件激活了炎症反应途径，降低了辅活化物水平，并对PR功能产生了负面影响。在最近的研究中，我们观察到PR辅助激活因子、CREB结合蛋白(CBP)和类固醇受体辅助激活因子(SRC)家族成员在分娩妇女子宫肌层和足月妊娠小鼠子宫组织中的组蛋白乙酰化水平显著下降。CBP和几个SRC家族成员具有组蛋白乙酰化酶活性，保持着开放的染色质结构。注射了组蛋白脱乙酰酶抑制剂的妊娠小鼠近期表现出子宫中组蛋白乙酰化增加和分娩延迟，这表明辅助激活因子的减少在启动分娩中具有重要的功能。我们还获得了有趣的数据，表明主要的肺表面活性蛋白SP-A，一种参与先天性免疫反应的C型凝集素，在胎儿肺中受到发育调节，并在近期分泌到羊水中，发出分娩开始的信号。SP-A能激活羊水巨噬细胞表达核因子kappaB和白介素1β。这些来自胎儿的巨噬细胞迁移到怀孕的子宫，导致炎症反应和子宫核因子-kB的活性增加。我们认为，母体子宫内核因子-kB的增加既直接增加了促进子宫收缩的基因的表达，又负面地影响了PR维持子宫静止的能力，从而导致了分娩的开始。基于这些发现，提出了以下研究目标：(1)进一步明确SP-A及其相关的表面活性蛋白SP-D在临产过程中的作用；(2)研究SP-A在足月时激活羊水中巨噬细胞，从而激活母体子宫中的核因子-kappaB的受体和信号机制；(3)确定足月子宫肌层辅活化子表达下降的细胞和分子机制(S)，以及；(4)破译孕酮和核因子-kappaB调控靶基因的分子机制，这些靶基因控制子宫肌层的静止/收缩。我们相信，这项研究将为调节辅助激活因子下降的分子机制以及胎儿肺成熟和肺表面活性物质分泌在妊娠子宫内激活炎症反应通路中所起的作用提供重要的见解，最终导致分娩。

DESCRIPTION (provided by applicant): We postulate that in women, as well as other mammalian species, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, and that spontaneous labor is initiated or facilitated by a concerted series of biochemical events that activate inflammatory response pathways, reduce coactivator levels and negatively impact PR function. In recent studies, we observed a marked decline in the PR coactivators, CREB-binding protein (CBP) and members of the steroid receptor coactivator (SRC) family, and in histone acetylation in myometrium of women in labor and in uterine tissues of pregnant mice at term. CBP and several SRC family members have histone acetylase activity, which maintains an open chromatin structure. Pregnant mice injected with a histone deacetylase inhibitor near term manifested increased histone acetylation in the uterus and delayed parturition, suggesting the functional importance of the decline in coactivators in the initiation of parturition. We also obtained intriguing data to suggest that the major lung surfactant protein, SP-A, a C-type lectin involved in innate immune response, that is developmentally regulated in fetal lung and secreted into amniotic fluid near term, signals the initiation of labor. SP-A activates amniotic fluid macrophages to express nuclear factor KappaB (NF-KappaB) and interleukin-1beta (IL-1beta). These macrophages, which are of fetal origin, migrate to the pregnant uterus leading to an inflammatory response and increased uterine NF-KB activity. We suggest that the increase in NF-KB within the maternal uterus both directly increases expression of genes that promote uterine contractility and negatively impacts the capacity of the PR to maintain uterine quiescence, contributing to the onset of labor. Based on these findings, the following research objectives are proposed: (1) to further define the role of SP-A and of the related surfactant protein, SP-D, in the initiation of labor; (2) to characterize the receptors and signaling mechanisms whereby SP-A at term activates macrophages in amniotic fluid, resulting in activation of NF-KappaB in the maternal uterus; (3) to determine the cellular and molecular mechanism(s) for the decline in expression of coactivators within the myometrium at term, and; (4) to decipher the molecular mechanisms whereby progesterone and NF-KappaB regulate target genes that control quiescence/contractility of the myometrium. We believe that this research will provide important insight into the molecular mechanisms that mediate the decline in coactivators and the role played by maturation of the fetal lung and secretion of pulmonary surfactant in activation of inflammatory response pathways within the pregnant uterus that culminate in parturition.