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: 10373931
• 负责人: Sam Antonio MESIANO
• 金额: $ 48.83万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/10373931
• 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; Hormone Receptor; Human; Human Biology; IL8 gene; In Vitro; Induced Labor; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; Labor Onset; Lead; 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; Research; Response Elements; Risk; Role; Serine; Signal Pathway; Signal Transduction; Stimulus; Testing; Tissues; Transcription Factor AP-1; Uterus; Withdrawal; Woman; Work; base; clinically significant; effective therapy; experimental study; 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

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）在美国影响10-15％的怀孕，并导致大多数新生儿死亡率和发病率。为了防止PTB对人类分娩的控制需要更清晰的理解。在这方面，通过核P4受体（PR）同工型，PR-A和PR-B作用的类固醇骑士孕酮（P4）是关键因素。在大多数怀孕中，P4/PR会促进子宫静止并阻止劳动，并破坏P4/PR信号触发触发。但是，这些关键P4/PR作用的机制尚不清楚。子宫和妊娠时机中的感染/炎症是术语和早产的主要驱动因素，但是这些作用的机制也不确定。拟议的研究通过探索通过磷酸化形式的PR-A中的创新和P4/PR信号传导的机制来解决这些主要知识差距，我们假设我们假设在感染引起的分娩的因果途径中起着核心作用。我们已发表的初步数据表明，P4/PR-B通过与IL-1ß-反应基因子集的启动子的启动子的启动子的启动子的启动子上的转录活性并反映了激活蛋白1（AP-1）转录因子的转录活性，从而抑制了对促炎性刺激的肌层细胞反应。我们的数据还表明，丝氨酸-344/345基因座（PSER344/345-PRA）在磷酸化时进行P4/PR-A与AP-1相互作用，以破坏P4/PR-B抗炎活性。我们还发现，肌矩元素激活蛋白激酶（MAPK）催化肌层细胞中PSER344/345-PRA的产生，响应促炎性刺激。根据这些数据，我们假设：1）P4/PR-B通过与AP-1结合以抑制炎症基因启动子的子集的转录，从而在肌层细胞中发挥抗炎活性； 2）PSER344/345-PRA通过破坏PR-B/AP-1的相互作用抑制P4/PR-B抗炎活性，3）特定的MAPK催化肌层细胞中PSER344/345-PRA的产生，催化响应于促进刺激刺激。该假设将在人肌层细胞系和从剖腹产递送获得的人肌层，恒河猴和炎症诱导的分娩的小鼠模型中进行检验。将实现两个具体目标：具体目标1：确定p4/pr-b在肌层细胞中发挥抗炎活性的机制，以及如何受到PSER344/345-PRA的影响；和特定目标2：确定如何在肌层细胞中控制PSER344/345- PRA的产生。拟议的研究是新颖和开创性的，将提高人们对人类分娩的基本生物学的理解，并有助于开发有效的基于P4/PR的抗炎疗法，以促进子宫静止并防止早产。