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: 9054669
• 负责人: Sam Antonio MESIANO
• 金额: $ 32.25万
• 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/9054669
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocytes; Birth; 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 Intensive Care Units; Neonatal Mortality; Nuclear; 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 care; neonatal morbidity; neutrophil; new therapeutic target; prevent; promoter; receptor; research study; response; socioeconomics; steroid hormone; survival outcome; 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.

描述(申请人提供)：开发预防早产的治疗方法，这是新生儿发病率和死亡率的主要原因，需要清楚地了解将子宫肌层从放松状态转变为分娩状态的激素相互作用。在这种情况下，孕酮是一个主要的参与者，因为它促进了怀孕大部分时间的子宫肌层松弛，它的退出启动了分娩，孕激素预防降低了一部分妇女的早产发生率。这项拟议的研究通过确定孕酮如何通过与其受体PR-A和PR-B的相互作用来影响人类子宫肌层细胞的基因表达，来检验孕酮是如何发挥这些作用的。我们发表的数据表明，孕酮通过PR-B促进子宫肌层松弛，分娩是通过增加子宫肌层细胞PR-A的表达而开始的，这通过抑制PR-B的转录活性而导致功能性黄体酮停用。为了测试这一点 假设我们开发了一种人类子宫肌层细胞系，以检测PR-A和PR-B如何影响孕酮的基因组活动。我们发现孕酮具有抗炎作用，在PR-B占优势的细胞中抑制致炎基因的表达，而在PR-A占优势的细胞中具有相反的作用。这些效应似乎是由PR直接作用于促炎症基因的启动子和通过调节核因子B(NF？B)的活性而介导的；特别是通过增加主要的抑制因子I？B的表达。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，我们认为孕酮通过PR-B抑制核因子-B介导的促炎基因表达来促进子宫肌层松弛，而通过PR-A介导的促炎基因表达促进分娩。为了验证这一假设，我们将：1)确定孕酮如何通过其与PR-A和PR-B的相互作用影响基础和细胞因子诱导的前列腺素(PG)-内过氧化物合成酶2(Ptgs2；被选为典型的促分娩/促炎基因)和I？B在人类子宫肌层细胞中的表达(特定目标1)。我们将描述PR-A和PR-B在PTGS2和I？B启动子上相互作用的机制，以及它们如何调节NF-B的活性。从我们的研究中得出的另一个重要概念是，分娩相关的子宫肌层细胞PR-A表达的增加，这是人类分娩中的一个关键事件，是由PGF2上调的。具体目的2是确定PGF2影响人子宫肌层细胞PR-A表达的细胞内信号通路和顺式/反式调节因子。PGF2通过其受体影响PR-A表达的信号通路和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将被确定。这两个目标的实验将在人子宫肌层细胞系中进行，包括我们的对独立诱导剂反应表达PR-A和PR-B的细胞系，以及子宫肌层外植体和原代培养的肌层细胞。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/改进基于孕激素的疗法以防止早产所需的知识。

项目成果

Labour classified by cervical dilatation & fetal membrane rupture demonstrates differential impact on RNA-seq data for human myometrium tissues.

• DOI: 10.1371/journal.pone.0260119
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lai PF;Lei K;Zhan X;Sooranna G;Li JKH;Georgiou EX;Das A;Singh N;Li Q;Stanfield Z;Zhang G;Tribe RM;Mesiano S;Johnson MR
• 通讯作者: Johnson MR

Molecular evidence of functional progesterone withdrawal in human myometrium.

• DOI: 10.1038/ncomms11565
• 发表时间: 2016-05-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Nadeem L;Shynlova O;Matysiak-Zablocki E;Mesiano S;Dong X;Lye S
• 通讯作者: Lye S

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells.

炎症刺激增加子宫肌层细胞中孕酮受体 A 的稳定性和反式抑制活性。

• DOI: 10.1210/en.2016-1537
• 发表时间: 2017
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Peters,GregoryA;Yi,Lijuan;Skomorovska-Prokvolit,Yelenna;Patel,Bansari;Amini,Peyvand;Tan,Huiqing;Mesiano,Sam
• 通讯作者: Mesiano,Sam

Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition.

子宫肌层细胞中黄体酮受体反式抑制活性的控制：对人类分娩控制的影响。

• DOI: 10.1177/1933719117716775
• 发表时间: 2018
• 期刊: Reproductive sciences (Thousand Oaks, Calif.)
• 作者: Patel,Bansari;Peters,GregoryA;Skomorovska-Prokvolit,Yelenna;Yi,Lijuan;Tan,Huiqing;Yousef,Ahmed;Wang,Junye;Mesiano,Sam
• 通讯作者: Mesiano,Sam