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

项目 2 胎儿在炎症反应和损害中的作用

• 批准号: 6896285
• 负责人: CAROLE R MENDELSON
• 金额: $ 30.82万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896285
• 关键词: amniotic fluid; cell migration; chromatin immunoprecipitation; disease /disorder prevention /control; fusion gene; gel mobility shift assay; gene deletion mutation; gene expression; genetic regulation; genetically modified animals; human subject; immune response; inflammation; laboratory mouse; lectin; leukocyte activation /transformation; macrophage; molecular biology; muscle contraction; myometrium; nuclear factor kappa beta; nucleic acid sequence; premature labor; progesterone receptors; protein localization; protein structure function; tissue /cell culture

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.

我们假设，在女性以及其他哺乳动物物种中，子宫静止是通过增​​加孕酮受体（PR）转录活性来维持的，并且自发分娩是由一系列协调一致的生化事件启动或促进的，这些事件激活炎症反应途径，降低共激活剂水平并对 PR 功能产生负面影响。在最近的研究中，我们观察到 PR 共激活因子、CREB ​​结合蛋白 (CBP) 和类固醇受体共激活因子 (SRC) 家族成员以及临产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显着下降。 CBP 和几个 SRC 家族成员具有组蛋白乙酰化酶活性，可维持开放的染色质结构。近期注射组蛋白脱乙酰酶抑制剂的怀孕小鼠表现出子宫中组蛋白乙酰化增加和分娩延迟，这表明共激活剂下降在分娩开始时的功能重要性。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（一种参与先天免疫反应的 C 型凝集素）在胎儿肺部发育中受到调节，并在近期分泌到羊水中，发出临产开始的信号。 SP-A 激活羊​​水巨噬细胞表达核因子 kappaB (NF-kappaB) 和白细胞介素 1beta (IL-1beta)。这些源自胎儿的巨噬细胞迁移到怀孕子宫，导致炎症反应和子宫 NF-κB 活性增加。我们认为，母体子宫内 NF-kappaB 的增加既会直接增加促进子宫收缩的基因表达，也会对 PR 维持子宫静止的能力产生负面影响，从而促进临产。基于这些发现，提出以下研究目标：（1）进一步明确SP-A和相关表面活性剂的作用 蛋白质 SP-D，在分娩开始时；(2) 表征足月 SP-A 激活羊​​水中巨噬细胞的受体和信号传导机制，从而导致母体子宫中 NF-κB 的激活； (3) 确定足月子宫肌层内共激活因子表达下降的细胞和分子机制； (4) 破译黄体酮和NF-κB调节控制子宫肌层静止/收缩性的靶基因的分子机制。我们相信这项研究 将为介导共激活剂下降的分子机制以及胎儿肺成熟和肺表面活性剂分泌在怀孕子宫内炎症反应途径激活（最终导致分娩）中所起的作用提供重要的见解。