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：
10620677
负责人：
Sam Antonio MESIANO
金额：
$ 48.37万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10620677
关键词：
Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Binding Biological Assay Biological Models Birth Cell Line Cells Cesarean section Complex Data Development Discipline of obstetrics Environment Fetal Development Freezing Generations Genes Genetic Transcription Goals Gravid Hormonal Hormones Human Human Biology IL8 gene In Vitro Induced Labor Infection Inflammation Inflammatory Knowledge Labor Onset Link Macaca mulatta Maps Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mus Myometrial Neonatal Intensive Care Units Neonatal Mortality Nuclear PTGS2 gene Pathway interactions Phase Phosphorylation Play Pregnancy Premature Birth Premature Labor Process Progesterone Progesterone Receptors Protein Isoforms Protein Kinase Publishing Reagent Receptor Signaling Regulation Relaxation Repression Research Response Elements Risk Role Serine Signal Pathway Signal Transduction Stimulus Testing Tissues Transcription Factor AP-1 Uterus Withdrawal Woman Work clinically significant effective therapy experimental study gene repression in vivo innovation intrauterine infection mouse model myometrium neonatal morbidity new therapeutic target novel premature prevent promoter receptor response socioeconomics steroid hormone stressor transcription factor uterine smooth muscle cell

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。为了预防早产，需要更清楚地了解人类分娩的激素控制。 P4) 通过核 P4 受体 (PR) 亚型 PR-A 和 PR-B 发挥作用，对于大多数妊娠来说，P4/PR 促进子宫静止。然而，这些关键 P4/PR 作用的机制尚不清楚，子宫和妊娠组织的感染/炎症是足月和早产的主要驱动因素。所提出的研究通过探索一种通过我们捕获的磷酸化形式的 PR-A 将炎症与子宫肌层细胞中的 P4/PR 信号传导联系起来的机制来解决这些主要的知识空白。我们发表的初步数据表明，P4/PR-B 通过与激活蛋白 1 (AP-1) 转录相互作用并抑制其转录活性，抑制子宫肌细胞对促炎刺激的反应。我们的数据还表明，P4/PR-A 在丝氨酸 344/345 位点磷酸化。 (pSer344/345-PRA) 与 AP-1 相互作用，破坏 P4/PR-B 抗炎活性我们还发现，丝裂原激活蛋白激酶 (MAPK) 会催化子宫肌细胞中 pSer344/345-PRA 的生成。根据我们研究的数据，P4/PR-B 通过与 AP-1 结合在子宫肌细胞中发挥抗炎活性。抑制炎症基因启动子子集的转录；2) pSer344/345-PRA 通过破坏 PR-B/AP-1 相互作用来抑制 P4/PR-B 抗炎活性，以及 3) pSer344/345-PRA 的生成子宫肌层细胞中的炎症反应是由特定的 MAPK 催化的，以响应促炎症刺激。这一假设将在人类子宫肌细胞系和获得的人类子宫肌层中进行测试。剖腹产以及诱导炎症分娩的恒河猴和小鼠模型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其作用机制。受 pSer344/345-PRA 的影响；以及具体目标 2：确定如何在子宫肌层细胞中控制 pSer344/345-PRA 的生成。该研究具有新颖性和开创性，将增进对人类分娩基本生物学的理解，并有助于开发基于 P4/PR 的有效抗炎疗法，以促进子宫静止并预防早产。