Fetal Cell Senescence Signals Initiation of Parturition

胎儿细胞衰老标志着分娩的开始

基本信息

批准号：
9901548
负责人：
RAMKUMAR MENON
金额：
$ 13.32万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-20 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901548
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 Exposure to 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 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 Uterus Venous Vesicle Withdrawal aged amnion base clinical material cytokine cytotrophoblast exosome experimental study fetal fetus cell myometrium non-histone protein novel novel therapeutics p38 Mitogen Activated Protein Kinase particle prevent progesterone receptor A progesterone receptor B public health relevance receptor response senescence therapy design trophoblast

项目摘要

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（由申请人提供）：足月胎儿细胞衰老是对氧化应激（OS）的自然生理反应，氧化应激是成熟胎儿代谢需求增加的结果，早产的各种危险因素与氧化应激诱导的衰老有关。我们的试验数据表明，胎儿细胞衰老导致警报蛋白 HMGB1（一种非组蛋白）从细胞核转移到细胞质，并在细胞质中被乙酰化和修饰。通过胞吐作用释放（“游离”HMGB1）或封装在外泌体中，通过多囊泡内体与质膜融合形成并挤出，在胎膜中充当促炎细胞因子。，它通过 TLR2 介导的 p38 MAPK 激活增强胎儿细胞衰老和相关的“无菌”炎症反应。 HMGB1 激活 p38 MAPK，导致孕激素受体 (PR) 同工型 A 上调，增加 COX-2 表达和心肌细胞炎症，HMGB1 还建立了正操作系统反馈环，加速羊水细胞衰老。胎膜通过扩散或通过外泌体运输，通过 p38 MAPK 引起子宫肌层激活，从而增加 PR-A 与PR-B，导致功能性黄体酮撤退并引发分娩。该假设将在 2 个具体目标中进行测试。具体目标 1 将确定 OS 如何刺激胎膜细胞衍生的 HMGB1 分泌，作为游离蛋白或包装并输出。具体目标 2 将确定胎儿膜细胞响应 OS 产生的游离或外泌体 HMGB1 如何诱导功能性黄体酮戒断和原发性肌层收缩性。转化的人羊膜、绒毛膜滋养层和子宫肌层细胞以及胎膜和子宫肌层器官培养物将暴露于 OS 诱导剂。使用分子和细胞生物学方法，我们将定量 OS 诱导的胎儿细胞衰老、HMGB1 释放、外泌体包装、外泌体-HMGB1 分泌方向、通过 p38 MAPK 的信号传导、PR 亚型转换和子宫肌层激活此外，我们还将量化 HMGB1 的浓度。本研究将评估我们储存的足月产和早产 (PTB) 胎儿母体生物液（羊水、外周和母体子宫静脉血浆以及胎儿脐带血浆）中的外泌体-HMGB1，以将其分布与确定的妊娠结局相关联。响应胎儿 OS 触发分娩的胎儿-母体信号机制。识别新的途径和生物分子应该为筛查、诊断和降低 PTB 的风险提供新的目标。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Placental Exosomes During Gestation: Liquid Biopsies Carrying Signals for the Regulation of Human Parturition.

妊娠期间的胎盘外泌体：携带调节人类分娩信号的液体活检。

DOI：
10.2174/1381612824666180125164429
发表时间：
2024-09-13
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
C. Salomon;Zarin Nuzhat;C. Dixon;R. Menon
通讯作者：
R. Menon

Initiation of human parturition: signaling from senescent fetal tissues via extracellular vesicle mediated paracrine mechanism.

人类分娩的启动：来自衰老胎儿组织的信号通过细胞外囊泡介导的旁分泌机制。

DOI：
发表时间：
2019-07
期刊：
影响因子：
0
作者：
Menon; Ramkumar
通讯作者：
Ramkumar

Cervix Stromal Cells and the Progesterone Receptor A Isoform Mediate Effects of Progesterone for Prepartum Remodeling.

子宫颈基质细胞和孕酮受体 A 异构体介导孕酮对产前重塑的影响。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Heuerman, Anne C;Hollinger, Trevor T;Menon, Ramkumar;Mesiano, Sam;Yellon, Steven M
通讯作者：
Yellon, Steven M

Quantitative Proteomics by SWATH-MS of Maternal Plasma Exosomes Determine Pathways Associated With Term and Preterm Birth.

通过 SWATH-MS 对母体血浆外泌体进行定量蛋白质组学，确定与足月和早产相关的途径。

DOI：
10.1210/en.2018-00820
发表时间：
2019-03-01
期刊：
Endocrinology
影响因子：
4.8
作者：
R. Menon;C. Dixon;Samantha Sheller;S. Fortunato;G. Saade;C. Palma;A. Lai;Dominic Guanzon;C. Salomon
通讯作者：
C. Salomon

Differences in cord blood extracellular vesicle cargo in preterm and term births.

早产儿和足月儿脐带血细胞外囊泡货物的差异。