Project 2 ROLE OF THE FETUS IN THE INFLAMMATORY RESPONSE AND COMPROMISE OF

我们假设，在妇女，以及其他哺乳动物物种，子宫静止是通过增加孕激素受体（PR）的转录活性，自发劳动启动或促进了一系列协调的生化事件，激活炎症反应途径，降低辅激活因子水平和PR功能产生负面影响。在最近的研究中，我们观察到PR辅激活因子，CREB结合蛋白（CBP）和类固醇受体辅激活因子（SRC）家族成员，以及分娩妇女子宫肌层和足月妊娠小鼠子宫组织中组蛋白乙酰化的显着下降。 CBP和几个SRC家族成员具有组蛋白乙酰化酶活性，其维持开放的染色质结构。近期注射组蛋白去乙酰化酶抑制剂的妊娠小鼠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在分娩启动中的功能重要性下降。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，C型凝集素参与先天免疫反应，这是发育调节胎儿肺和分泌到羊水近期，信号的劳动开始。SP-A激活羊水巨噬细胞表达核因子κ B（NF-κ B）和白细胞介素-1 β（IL-1 β）。这些巨噬细胞是胎儿来源的，迁移到妊娠子宫，导致炎症反应和子宫NF-κ B活性增加。我们认为母体子宫内NF-κ B的增加直接增加了促进子宫收缩的基因的表达，并对PR维持子宫静止的能力产生负面影响，从而促进分娩的开始。在此基础上，提出了以下研究目标：（1）进一步明确SP-A及其相关表面活性剂的作用 蛋白SP-D在分娩启动中的作用;（2）表征SP-A在足月时激活羊水中巨噬细胞，导致母体子宫中NF-κ B激活的受体和信号传导机制;（3）确定足月时子宫肌层内辅激活因子表达下降的细胞和分子机制;（4）解释孕酮和NF-κ B调节控制子宫肌层静止/收缩的靶基因的分子机制。我们相信这项研究 将提供重要的深入了解介导的分子机制，在辅激活因子的下降和胎儿肺的成熟和分泌的肺表面活性物质在激活炎症反应途径在妊娠子宫内，最终在分娩中发挥的作用。

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 acetytation 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-kappaB activity. We suggest that the increase in NF-kappaB 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.