A novel mechanism for inflammation-induced preterm birth via PR-A phosphorylation

通过 PR-A 磷酸化炎症诱导早产的新机制

基本信息

  • 批准号:
    10373931
  • 负责人:
  • 金额:
    $ 48.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Preterm birth (PTB) affects 10-15% of pregnancies in the US and causes the majority of neonatal mortality and morbidity. To prevent PTB a clearer understanding is needed of the hormonal control of human parturition. In this regard, the steroid hormone progesterone (P4) acting via the nuclear P4 receptor (PR) isoforms, PR-A and PR-B, is a critical factor. For most of pregnancy P4/PR promotes uterine quiescence and blocks labor, and disruption of P4/PR signaling triggers parturition. The mechanism for these critical P4/PR actions are, however, unclear. Infection/inflammation in the uterine and gestational tissues are major drivers of term and preterm parturition, but the mechanism for these effects are also uncertain. The proposed research addresses these major knowledge gaps by exploring a mechanism linking inflammation and P4/PR signaling in myometrial cells via a phosphorylated form of PR-A that we hypothesize plays a central role in the causal pathway for inflammation-induced parturition. Our published and preliminary data suggest that P4/PR-B inhibits myometrial cell responsiveness to pro-inflammatory stimuli by interacting with and repressing the transcriptional activity of the activator protein 1 (AP-1) transcription factors at promotors of a subset of IL-1ß-responsive genes. Our data also suggest that P4/PR-A upon phosphorylation at the serine-344/345 locus (pSer344/345-PRA) interacts with AP-1 to disrupt P4/PR-B anti-inflammatory activity. We also found that generation of pSer344/345-PRA in myometrial cells is catalyzed by mitogen activated protein kinases (MAPKs) in response to pro-inflammatory stimuli. Based on those data we hypothesize that: 1) P4/PR-B exerts anti-inflammatory activity in myometrial cells by binding to AP-1 to inhibit transcription at a subset of inflammatory gene promoters; 2) pSer344/345-PRA inhibits P4/PR-B anti-inflammatory activity by disrupting the PR-B/AP-1 interaction, and 3) generation of pSer344/345-PRA in myometrial cells is catalyzed by specific MAPKs in response to pro-inflammation stimuli. This hypothesis will be tested in human myometrial cell lines and human myometrium obtained from c-section deliveries, and Rhesus macaque and mouse models of inflammation induced parturition. Two Specific Aims will be achieved: Specific Aim 1: Determine the mechanism by which P4/PR-B exerts anti-inflammatory activity in myometrial cells and how this is affected by pSer344/345-PRA; and Specific Aim 2: Determine how pSer344/345- PRA generation is controlled in myometrial cells. The proposed research is novel and groundbreaking and will advance understanding of the fundamental biology of human parturition and contribute to the development of effective P4/PR-based anti-inflammatory therapies to promote uterine quiescence and prevent preterm birth.
早产(PTB)影响美国10-15%的妊娠,并导致大多数新生儿死亡和发病。为了预防PTB,需要更清楚地了解人类分娩的激素控制。在这方面,类固醇激素孕酮(P4)通过核P4受体(PR)亚型PR-A和PR-B起作用,是一个关键因素。在大多数妊娠期,P4/PR促进子宫静止并阻断分娩,P4/PR信号传导的中断触发分娩。然而,这些重要的P4/PR行动的机制尚不清楚。子宫和妊娠组织中的感染/炎症是足月分娩和早产的主要驱动因素,但这些影响的机制也不确定。拟议的研究通过探索子宫肌层细胞中炎症和P4/PR信号转导通过磷酸化形式的PR-A的机制来解决这些主要的知识空白,我们假设PR-A在炎症诱导分娩的因果途径中起着核心作用。我们已发表的和初步的数据表明,P4/PR-B抑制子宫肌层细胞的反应性,促炎性刺激,通过相互作用和抑制激活蛋白1(AP-1)转录因子的转录活性在IL-1 β反应基因的一个子集的启动子。我们的数据还表明,P4/PR-A在丝氨酸-344/345位点(pSer 344/345-PRA)磷酸化后与AP-1相互作用以破坏P4/PR-B抗炎活性。我们还发现,在子宫肌层细胞中pSer 344/345-PRA的产生是由促炎刺激的促分裂原活化蛋白激酶(MAPK)催化的。基于这些数据,我们假设:1)P4/PR-B通过与AP-1结合抑制炎性基因启动子的转录而在子宫肌层细胞中发挥抗炎活性; 2)pSer 344/345-PRA通过破坏PR-B/AP-1相互作用抑制P4/PR-B抗炎活性,和3)子宫肌层细胞中pSer 344/345-PRA的产生是由特异性MAPK响应促炎症刺激而催化的。将在从剖腹产分娩获得的人子宫肌层细胞系和人子宫肌层以及炎症诱导分娩的恒河猴和小鼠模型中测试该假设。将实现两个具体目标:具体目标1:确定P4/PR-B在子宫肌层细胞中发挥抗炎活性的机制以及pSer 344/345-PRA如何影响这一机制;具体目标2:确定子宫肌层细胞中pSer 344/345- PRA的产生如何受到控制。拟议的研究是新颖的和开创性的,将促进对人类分娩基本生物学的理解,并有助于开发有效的基于P4/PR的抗炎疗法,以促进子宫静止和预防早产。

项目成果

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Sam Antonio MESIANO其他文献

Sam Antonio MESIANO的其他文献

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{{ truncateString('Sam Antonio MESIANO', 18)}}的其他基金

Paracrine control of the maternal-fetal interface critical for pregnancy wellness
母胎界面的旁分泌控制对妊娠健康至关重要
  • 批准号:
    10753130
  • 财政年份:
    2023
  • 资助金额:
    $ 48.83万
  • 项目类别:
A novel mechanism for inflammation-induced preterm birth via PR-A phosphorylation
通过 PR-A 磷酸化炎症诱导早产的新机制
  • 批准号:
    10620677
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
A novel mechanism for inflammation-induced preterm birth via PR-A phosphorylation
通过 PR-A 磷酸化炎症诱导早产的新机制
  • 批准号:
    10096304
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
Development of therapeutics to prevent spontaneous preterm birth
开发预防自发性早产的疗法
  • 批准号:
    10320868
  • 财政年份:
    2019
  • 资助金额:
    $ 48.83万
  • 项目类别:
Development of therapeutics to prevent spontaneous preterm birth
开发预防自发性早产的疗法
  • 批准号:
    10549723
  • 财政年份:
    2019
  • 资助金额:
    $ 48.83万
  • 项目类别:
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:
    8657403
  • 财政年份:
    2012
  • 资助金额:
    $ 48.83万
  • 项目类别:
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:
    8841387
  • 财政年份:
    2012
  • 资助金额:
    $ 48.83万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 48.83万
  • 项目类别:
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:
    8523944
  • 财政年份:
    2012
  • 资助金额:
    $ 48.83万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 48.83万
  • 项目类别:

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