Role of nuclear progesterone receptors in the control of human parturition

核孕酮受体在控制人类分娩中的作用

• 批准号: 8369058
• 负责人: Sam Antonio MESIANO
• 金额: $ 32.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369058
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocytes; Birth; Caring; Cell Line; Cell Surface Receptors; Cells; Complement Factor B; Complex; Data; Development; Dinoprost; Elements; Environment; Event; Feedback; Fetal Development; Future; Gene Expression; Genes; Genomics; Goals; Health; Hormonal; Hormones; Human; Incidence; Indium; Induced Labor; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-8; Interleukins; Knowledge; Link; Mediating; Molecular; Molecular Biology; Muscle Cells; Myometrial; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Nuclear; Outcome; PTGS2 gene; Phase; Pregnancy; Premature Birth; Premature Infant; Premature Labor; Prevention; Problem Solving; Process; Progesterone; Progesterone Receptors; Progestins; Prophylactic treatment; Proteins; Publishing; Relaxation; Research; Role; Signal Pathway; Source; Stimulus; Term Birth; Testing; Therapeutic; Tissues; Up-Regulation; Uterus; Withdrawal; Woman; base; cyclooxygenase 2; cytokine; effective therapy; improved; inhibitor/antagonist; myometrium; neonatal morbidity; neutrophil; new therapeutic target; prevent; promoter; receptor; research study; response; socioeconomics; steroid hormone; therapy development; transcription factor; uterine contractility

DESCRIPTION (provided by applicant): The development of therapies to prevent preterm birth, which is the major cause of neonatal morbidity and mortality, requires a clear understanding of the hormonal interactions that transform the myometrium from the relaxed to the laboring state. In this context, progesterone is a major player because it promotes myometrial relaxation for most of pregnancy, its withdrawal initiates labor, and progestin prophylaxis decreases the incidence of preterm birth in a subset of women. The proposed research examines how progesterone exerts these actions by determining how, via its interaction with its receptors, PR-A and PR-B, it affects gene expression in human myometrial cells. Our published data suggest that progesterone promotes myometrial relaxation via PR-B and that labor is initiated by increased myometrial cell expression of PR-A, which causes functional progesterone withdrawal by inhibiting the transcriptional activity of PR-B. To test this hypothesis we developed a human myometrial cell line to examine how PR-A and PR-B affect genomic actions of progesterone. We found that progesterone was anti-inflammatory and inhibited the expression of pro- inflammatory genes in PR-B-dominant cells but had the opposite effect in PR-A-dominant cells. The effects appeared to be mediated by direct actions of the PRs at the promoters of pro-inflammatory genes and by modulation of nuclear factor -¿B (NF¿B) activity; especially by increased expression of I¿B¿, a major repressor if NF¿B. These findings are important because labor is thought to be sequelae of myometrial inflammation. Thus we propose that progesterone via PR-B promotes myometrial relaxation by inhibiting NF-¿B-mediated pro-inflammatory gene expression, whereas it promotes labor via PR-A-mediated up-regulation of pro- inflammatory gene expression. To test this hypothesis we will: 1) determine how progesterone via its interaction with PR-A and PR-B affects basal and cytokine-induced expression of prostaglandin (PG) - endoperoxide synthase 2 (PTGS2; chosen as a prototypical pro-labor/pro-inflammatory gene) and I¿B¿ in human myometrial cells (Specific Aim 1). We will characterize the mechanism by which PR-A and PR-B interact at the PTGS2 and I¿B¿ promoters, and how they may modulate NF-¿B activity. Another important concept to arise from our research is that the parturition-associated increase in myometrial cell PR-A expression, which is a key event in human parturition, is up-regulated by PGF2¿. Specific Aim 2 wil be to identify the intracellular signaling pathways and cis/trans regulators through which PGF2¿ affects PR-A expression in human myometrial cells. The signaling pathways through which PGF2¿ via its receptor affects PR-A expression and the cis elements in the PR-A promoter and the transcription factors acting on those elements through which PGF2¿ induces PR-A expression will be identified. Experiments for both aims will be performed in human myometrial cell lines, including our line that expresses PR-A and PR-B in response to independent inducers, and myometrial explant and primary myocyte cultures of term myometrium. The research will advance understanding of how progesterone controls human pregnancy and parturition and provide knowledge needed to develop/improve progestin-based therapies to prevent preterm birth. PUBLIC HEALTH RELEVANCE: Preterm birth is a major socioeconomic problem that affects 10-15% of pregnancies and causes 70-80% of neonatal mortality and morbidity. Despite advances in neonatal care that have improved survival outcomes, the confounding problems due to preterm birth profoundly affect a preterm infant's future health. Clearly, the final phase o fetal development is best achieved in the womb environment rather than in the neonatal intensive care unit. To this end, we must prevent and/or suppress preterm labor. However, current therapies to suppress preterm labor are generally ineffective. To solve this problem we must fill the knowledge-gaps that limit our capacity to develop effective treatments for preterm labor. To this end, our goal is to elucidate the hormonal interactions that control uterine contractility during human pregnancy. In this context the steroid hormone progesterone is critical. This proposal addresses the molecular mechanisms by which the nuclear progesterone receptors PR-A and PR-B mediate progesterone actions in human myometrial cells. A clear understanding of this process may reveal novel therapeutic targets for the suppression of preterm labor and the prevention of preterm birth.

描述（由申请人提供）：预防早产是新生儿发病和死亡的主要原因，开发治疗方法需要清楚地了解将子宫肌层从松弛状态转变为分娩状态的激素相互作用。黄体酮是一个主要的参与者，因为它在怀孕的大部分时间里促进子宫肌层松弛，促进分娩，并且黄体酮预防可以降低部分女性早产的发生率。拟议的研究通过确定黄体酮如何通过其受体 PR-A 和 PR-B 相互作用影响人类子宫肌层细胞中的基因表达来研究黄体酮如何发挥这些作用。我们发表的数据表明，黄体酮通过 PR-B 和 PR-B 促进子宫肌层松弛。分娩是由 PR-A 的子宫肌细胞表达增加引发的，PR-A 的表达增加通过抑制 PR-B 的转录活性导致功能性黄体酮撤退。 假设我们开发了一种人类子宫肌层细胞系来检查 PR-A 和 PR-B 如何影响孕酮的基因组作用。我们发现孕酮具有抗炎作用，并抑制 PR-B 主导细胞中促炎基因的表达。在 PR-A 主导的细胞中产生相反的作用，这种作用似乎是由 PR 对促炎基因启动子的直接作用和核因子 -¿ 的调节介导的。 B (NF¿B) 活性；特别是通过增加 I¿ B?? , 一个主要的阻遏蛋白如果 NF¿ B. 这些发现很重要，因为分娩被认为是子宫肌层炎症的后遗症，因此我们提出孕酮通过 PR-B 通过抑制 NF-¿ 促进子宫肌层松弛。 B 介导的促炎基因表达，而它通过 PR-A 介导的促炎基因表达上调促进分娩。为了检验这一假设，我们将：1) 确定孕酮如何通过其与 PR-A 和 PR 的相互作用来促进分娩。 -B 影响前列腺素 (PG) - 内过氧化物合酶 2（PTGS2；选择作为典型的促分娩/促炎基因）和 I¿ 的基础和细胞因子诱导的表达B??在人类子宫肌层细胞中（具体目标 1），我们将描述 PR-A 和 PR-B 在 PTGS2 和 I¿ 上相互作用的机制。 B??启动子，以及它们如何调节 NF-¿我们研究中提出的另一个重要概念是，与分娩相关的子宫肌细胞 PR-A 表达增加，这是人类分娩的一个关键事件，受到 PGF2 的上调。具体目标 2 是确定 PGF2 所通过的细胞内信号传导途径和顺式/反式调节因子影响人子宫肌层细胞中 PR-A 的表达。PGF2 所通过的信号通路。通过其受体影响 PR-A 表达和 PR-A 启动子中的顺式元件以及作用于这些元件的转录因子，PGF2通过其作用诱导 PR-A 表达的实验将在人类子宫细胞系中进行，包括我们的响应独立诱导物表达 PR-A 和 PR-B 的细胞系，以及足月子宫肌层的子宫肌层外植体和原代肌细胞培养物。该研究将增进对黄体酮如何控制人类怀孕和分娩的理解，并提供开发/改进基于黄体酮的疗法以预防早产所需的知识。 公共卫生相关性：早产是一个主要的社会经济问题，影响 10-15% 的妊娠，并导致 70-80% 的新生儿死亡率和发病率。显然，胎儿发育的最后阶段最好在子宫环境中而不是在新生儿重症监护室中实现。为此，我们必须预防。然而，目前抑制早产的疗法通常无效，为了解决这个问题，我们必须填补限制我们开发有效早产治疗方法的知识空白。阐明在人类怀孕期间控制子宫收缩力的激素相互作用，在这种情况下，类固醇激素黄体酮至关重要。该提案阐述了核黄体酮受体 PR-A 和 PR-B 介导黄体酮的分子机制。清楚地了解这一过程可能会揭示抑制早产和预防早产的新治疗靶标。