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（由适用提供）：防止早产的疗法的发展，这是新生儿发病率和死亡率的主要原因，需要清楚地理解从放松状态转化为肌层变为劳动状态的骑马相互作用。在这种情况下，孕酮是主要参与者，因为它可以促进大部分怀孕的肌层松弛，其戒断会促进劳动，而预防孕激素会减少女性子集中早产的事件。拟议的研究检查孕酮如何通过与其受体的相互作用PR-A和PR-B确定如何影响人肌层细胞中的基因表达。我们已发表的数据表明，孕酮通过PR-B促进了肌层松弛，并且通过PR-A的肌层细胞表达增加而引发劳动，从而通过抑制PR-B的转录活性引起功能性孕激素的戒断。测试这个 假设我们开发了人体肌层细胞系，以研究PR-A和PR-B如何影响孕酮的基因组作用。我们发现孕酮是抗炎的，并抑制了PR-B-B含量细胞中促炎基因的表达，但在PR-A含量的细胞中具有相反的作用。该作用似乎是由PRS在促炎基因启动子和核因子 - b（nf¿b）活性的调节中的直接作用介导的。特别是通过增加i贝的表达，如果NF¿B。这些发现很重要，因为劳动被认为是肌层感染的后遗症。我们提出，通过PR-B，孕酮通过抑制NF-介导的促炎基因表达来促进肌层松弛，而它通过PR-A介导的促炎基因表达的上调促进劳动。为了检验该假设，我们将：1）确定孕酮与PR-A和PR-B的相互作用如何影响碱性和细胞因子诱导的前列腺素的表达（PG） - 内过氧化物合酶2（PTGS2； PTGS2；选择为原型性的Pro-Labor/Pro-Labor/Pro-Pro摄取的基因）和IM MyOmememememetial（特定于人类的imotial Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Aim Extim 1。我们将表征PR-A和PR-B在PTGS2和Ib¿启动子上相互作用的机制，以及它们如何调节NF-€B活性。我们的研究要引起的另一个重要概念是，PGF2€上调了与人肌层细胞PR-A表达相关的增加，这是人类分娩中的关键事件。具体目标2将确定细胞内信号通路和顺式/反式调节剂，PGF2 pr-a会影响人肌层细胞中的PR-A表达。 PGF2通过其受体通过PR-A表达和PR-A启动子中的顺式元素以及作用于PGF2诱导PR-A表达的那些元素的转录因子。这两个目标的实验都将在人体肌层细胞系中进行，包括我们的线，该线表达对独立诱导剂的响应，以及术语子宫骨术的肌层外植体和原发性肌细胞培养物。这项研究将促进对孕酮如何控制人类怀孕和分娩的理解，并提供开发/改善基于孕激素的疗法以防止早产所需的知识。 公共卫生相关性：早产是一个主要的社会经济问题，影响了10-15％的怀孕，并导致70-80％的新生儿死亡率和发病率。尽管新生儿护理的进步改善了生存结果，但由于早产而引起的混乱问题深远影响了早产儿的未来健康。显然，在子宫环境中，最好在新生儿重症监护室中实现最终的O胎儿发育。为此，我们必须预防和/或抑制早产。但是，当前抑制早产的疗法通常无效。为了解决这个问题，我们必须填补知识差距，以限制我们为早产劳动开发有效治疗的能力。为此，我们的目标是阐明在人类怀孕期间控制子宫收缩力的骑马相互作用。在这种情况下，类固醇孕酮至关重要。该建议探讨了核孕激素受体PR-A和PR-B介导人肌层细胞中孕酮作用的分子机制。对这一过程的清晰了解可能揭示了抑制早产和预防早产的新型治疗靶标。