Fetal Cell Senescence Signals Initiation of Parturition

胎儿细胞衰老标志着分娩的开始

• 批准号: 9276045
• 负责人: RAMKUMAR MENON
• 金额: $ 14.22万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276045
• 关键词: Acetylation; Address; Affect; Aging; Amniotic Fluid; Apical; Area; B-Lymphocytes; Biochemistry; Biological; Biological Markers; Birth; Cell Aging; Cell Nucleus; Cell membrane; Cells; Chorion; Cytosol; Data; Diagnosis; Diffusion; Electron Microscopy; Encapsulated; Endosomes; Exocytosis; Feedback; Fetal Membranes; Fetal Tissues; Fetus; Flow Cytometry; Genes; Genetic Transcription; HMGB1 Protein; Human; Immune response; Immunoblotting; Inflammation; Inflammatory; Knowledge; Labor Onset; Lead; Liquid substance; MAP Kinase Gene; MAPK14 gene; Mediating; Metabolic; Molecular; Mothers; Muscle Cells; Myometrial; Organ Culture Techniques; Oxidants; Oxidative Stress; PTGS2 gene; Pathway interactions; Peripheral; Pharmacology; Phenotype; Physiological; Plasma; Pregnancy; Pregnancy Outcome; Pregnancy Tests; Premature Birth; Premature Labor; Premature aging syndrome; Process; Progesterone; Progesterone Receptors; Protein Isoforms; Proteins; Public Health; RNA Interference; Reaction; Recombinants; Research; Risk; Risk Factors; Role; Signal Transduction; Sterility; Stimulus; TLR2 gene; TLR4 gene; Term Birth; Testing; Tissues; Toll-like receptors; Up-Regulation; Venous; Vesicle; Withdrawal; aged; amnion; base; clinical material; cytokine; cytotrophoblast; exosome; experimental study; fetal; fetus cell; mitogen-activated protein kinase p38; myometrium; non-histone protein; novel; novel therapeutics; particle; prevent; progesterone receptor A; progesterone receptor B; public health relevance; receptor; response; senescence; therapy design; trophoblast

 DESCRIPTION (provided by applicant): Fetal cell senescence at term is a natural physiologic response to oxidative stress (OS) that occurs as a result of increased metabolic demands by the maturing fetus. Various risk factors for preterm labor are associated with OS-induced senescence. Our pilot data suggest that fetal cell senescence causes the alarmin HMGB1 (a non-histone protein) to translocate from the nucleus to the cytosol. There it is modified by acetylation and released via exocytosis ("free" HMGB1) or encapsulated in exosomes, (30-100 nm particles) formed and extruded by multivesicular endosome fusion with the plasma membrane. Secreted HMGB1 functions as a proinflammatory cytokine in feto-maternal tissues. In the fetal membranes, it augments fetal cell senescence and an associated 'sterile' inflammatory reaction through TLR2-mediated p38 MAPK activation. In myocytes, HMGB1 activates p38 MAPK, resulting in upregulation of progesterone receptor (PR) isoform A and increased COX-2 expression and myocyte inflammation. A positive OS feedback loop is also established by HMGB1, accelerating amniocyte aging. Our core hypothesis posits that HMGB1 secreted from senescing fetal membranes, either by diffusion or transported via exosomes, causes myometrial activation through p38 MAPK, which in turn increases the ratio of PR-A to PR-B, leading to functional progesterone withdrawal and triggering the onset of labor. This hypothesis will be tested in 2 specific aims. Specific Aim 1 will determine how OS stimulates fetal membrane cell-derived HMGB1 secretion, as free protein or packaged and exported in exosomes, during human pregnancy and parturition. Specific Aim 2 will determine how free- or exosome-HMGB1 produced by fetal membrane cells in response to OS induces functional progesterone withdrawal and myometrial contractility. Primary and transformed human amnion, chorionic trophoblast, and myometrial cells, as well as fetal membrane and myometrial organ cultures, will be exposed to OS-inducing agents. Using molecular and cellular biological approaches we will quantitate OS-induced fetal cell senescence, HMGB1 release, exosome packaging, direction of exosome-HMGB1 secretion, signaling via p38 MAPK, PR isoform switching, and myometrial activation. Additionally, we will quantify the concentrations of exosome-HMGB1 in our banked feto-maternal biologic fluids (amniotic fluid, peripheral and maternal uterine venous plasma, and fetal cord plasma) from term and preterm births (PTB) to correlate their distribution with defined pregnancy outcomes. This study will evaluate a new feto-maternal signaling mechanism that triggers parturition in response to fetal OS. Identification of novel pathways and biomolecules should provide new targets to screen, diagnose, and reduce the risk of PTB.

 描述（由适用提供）：术语时的胎儿细胞感应是对氧化应激（OS）的自然生理反应，这是由于成熟胎儿的代谢需求增加而导致的。早产的各种风险因素与OS诱导的感应有关。我们的试点数据表明，胎儿细胞的感应会导致Alarmin HMGB1（一种非固定蛋白）从细胞核转移到细胞质。它通过乙酰化修饰，并通过胞吐作用（“游离” HMGB1）释放，或封装在外泌体（30-100 nm颗粒）中，形成并通过与质膜的多质内体融合形成并挤出。分泌的HMGB1充当胎儿组织中的促炎细胞因子。在胎儿膜中，它通过TLR2介导的P38 MAPK激活增强了胎儿细胞的感应和相关的“无菌”炎症反应。在肌细胞中，HMGB1激活p38 MAPK，导致孕酮受体（PR）同工型A上调，并增加COX-2表达和肌细胞注射。 HMGB1也建立了正OS反馈回路，加速了羊膜细胞衰老。我们的核心假设认为，通过扩散或通过外泌体传输的HMGB1从传感的胎儿膜中分泌，会通过p38 MAPK引起子宫肌层激活，进而增加PR-A与PR-B的比率，从而导致功能性孕酮撤离和触发劳动的发作。该假设将以两个特定目的进行检验。具体目标1将决定OS如何刺激胎儿细胞衍生的HMGB1分泌，作为自由蛋白或在人类妊娠和分娩期间外泌体中包装和出口的胎儿。特定的目标2将决定胎儿膜细胞对OS产生的自由或外泌体HMGB1如何诱导功能性孕激素戒断和肌层收缩力。原发性和转化的人羊膜，绒毛膜滋养细胞和肌层细胞以及胎儿膜和肌层器官培养物将暴露于OS诱导的药物。使用分子和细胞生物学方法，我们将定量OS诱导的胎儿细胞感应，HMGB1释放，外部包装，外部HMGB1分泌的方向，通过p38 MAPK信号传导，PR同工型切换和肌层激活。此外，我们将从学期和早产（PTB）（ptb）中量化银行的feto母亲生物学液（羊水，外周和材料静脉血浆以及胎儿血浆）中的外泌体-HMGB1浓度，以将其分布与已定义的妊娠相关联。这项研究将评估一种新的feto妇女信号传导机制，该机制可触发胎儿OS的分娩。新型途径和生物分子的识别应提供新的目标，以筛选，诊断和降低PTB的风险。