Role of the Fetus in the Initiation of Parturition

胎儿在​​分娩过程中的作用

• 批准号: 6817098
• 负责人: CAROLE R MENDELSON
• 金额: $ 14.63万
• 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: 2004-07-10 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817098
• 关键词: amniotic fluid; biological signal transduction; birth; cell migration; clinical research; embryo /fetus; female; gene expression; genetically modified animals; hormone regulation /control mechanism; human pregnant subject; laboratory mouse; lectin; lung development; macrophage; muscle contraction; myometrium; nuclear factor kappa beta; patient oriented research; progesterone; progesterone receptors; protein structure function; pulmonary surfactants; secretion; tissue /cell culture; toll like receptor; transcription factor; women' s health

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.

描述（由申请人提供）：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​​加的孕激素受体（PR）转录活性来维持的，并且自发性劳动是通过一系列的生物化学事件来发起或促进的，从而使炎症反应途径的一系列协同的生物化学事件降低了共同作用途径，降低了共同效果，并降低了共同效果。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剂（SRC）家族的成员以及劳动妇女子宫肌矩阵在劳动和孕妇的子宫内部的子宫内部乙酰化的成员以及孕妇的子宫肌矩阵的成员。 CBP和几个SRC家族成员具有组蛋白乙酰酶活性，可维持开放的染色质结构。注射组蛋白脱乙酰基酶抑制剂的孕妇近期表现出了子宫中组蛋白乙酰化的增加，并延迟了分娩，这表明共同激活剂在开始分娩时的功能重要性。我们还获得了有趣的数据，以表明主要的肺表面活性剂蛋白SP-A是一种参与先天免疫反应的C型凝集素，该凝集素在胎儿肺中受到发育调节，并将其分泌到近任期的羊水中，这表明劳动的开始。 SP-A激活羊水巨噬细胞以表达核因子Kappab（NF-KAPPAB）和白介素1Beta（IL-1Beta）。这些具有胎儿起源的巨噬细胞迁移到怀孕的子宫，导致炎症反应并增加子宫NF-KB活性。我们建议，母体子宫内NF-KB的增加都直接增加了促进子宫收缩力的基因表达，并对PR维持子宫静止的能力产生负面影响，从而有助于劳动的发作。根据这些发现，提出了以下研究目标：（1）进一步定义SP-A和相关表面活性剂蛋白SP-D在劳动启动中的作用； （2）表征受体和信号传导机制，从而使SP-A在学期中激活羊水中的巨噬细胞，从而导致母体子宫中NF-kappab的激活； （3）确定术语中肌矩阵内共激活剂表达下降的细胞和分子机制，并且； （4）解读了分子机制，从而使孕酮和NF-kappab调节靶基因，从而控制子宫肌层的静止/收缩力。我们认为，这项研究将为介导共激活因子下降的分子机制以及胎儿肺的成熟和分泌肺表面活性剂在孕妇子宫内激活炎症反应途径的作用而提供重要的见解。