Static state of epithelial mesenchymal transition in fetal membrane cells: a novel inflammatory pathway to parturition

胎儿膜细胞上皮间质转化的静态：一种新的分娩炎症途径

• 批准号: 9893012
• 负责人: RAMKUMAR MENON
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893012
• 关键词: Aging; Binding Proteins; Biological; Biological Assay; Birth; Cell Culture Techniques; Cell membrane; Cells; Characteristics; Complement Factor B; Cytokeratin 18; Data; E-Cadherin; Embryo; Endocrine; Environment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Equilibrium; Exposure to; Fetal Growth; Fetal Membranes; Fetal Tissues; Fetus; Gene Silencing; Growth Factor; Homeostasis; Hormones; Immune; In Vitro; Induced Labor; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; MAP3K7IP1 gene; MMP9 gene; Maintenance; Mechanics; Mediating; Membrane; Mesenchymal; Methods; Modeling; Molecular; N-Cadherin; Oxidative Stress; Pathologic; Pathway interactions; Phosphotransferases; Physiological; Play; Pregnancy; Premature Birth; Premature Labor; Prevention; Process; Production; Progesterone; RNA Interference; Reporting; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Structure; TWIST1 gene; Testing; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Uterus; Vimentin; Work; adverse pregnancy outcome; amnion; cell motility; epithelial to mesenchymal transition; experimental study; in utero; inhibitor/antagonist; injured; novel; p38 Mitogen Activated Protein Kinase; premature; preterm premature rupture of membranes; prevent; receptor; repaired; response; senescence; transcription factor; wound healing

ABSTRACT Fetal membranes (amniochorion) provide the structural framework and perform mechanical and protective functions during pregnancy. A progressive p38 mitogen-activated protein kinase (MAPK)-mediated senescence (mechanism of aging) occurs in fetal membranes. It is correlated with fetal growth and is accelerated at term due to increased oxidative stress (OS) in the intrauterine cavity. Senescence of fetal tissues causes inflammation that can promote labor; thus, membranes play a critical role in pregnancy and parturition. Throughout gestation, membranes maintain homeostasis by repairing themselves when cells are shed and the matrix is degraded. This remodeling process creates gaps and microfractures. At the cellular level, it remains unclear how the membranes' pluripotent amnion epithelial and mesenchymal cells repair the damaged sites. Since remodeling is essential for maintaining membrane homeostasis and preventing adverse pregnancy outcomes, understanding this process is critical. We have determined that injury to amnion epithelial cells (AEC) forces AEC proliferation and cell migration to rebuild injured sites, which is a normal physiologic response. Pilot data suggest that OS- and p38 MAPK-mediated senescence cause epithelial mesenchymal transition (EMT) and prevent tissue remodeling through increased production of TGFβ. We also determined that TGFβ plays dual functions: 1) induction of senescence by autophosphorylation of p38MAPK and 2) induction of EMT transcription factors to facilitate cellular and mechanical membrane disruption. These effects were reversed by progesterone (P4). We hypothesize that balanced tissue remodeling maintains fetal membrane homeostasis during pregnancy, but TGFβ increase due to overwhelming OS at term or in response to infection and inflammation (TNFα) at preterm causes an irreversible state of p38MAPK-mediated senescence and EMT that can promote membrane damage. Additionally, we hypothesize that during pregnancy, TGFβ-mediated transitions are balanced by progesterone (P4). We will test our hypotheses using 2 specific aims: Aim 1—To determine if LPS (infection) and TNFα (inflammation) can cause TGFβ -TAB1-p38MAPK signaling pathways, leading to EMT in AEC. Aim 2—To determine the regulatory role of P4 in LPS and TNFα-mediated TGFβ production and its ability to reduce EMT. Maintenance of membrane homeostasis by TGFβ-P4 during normal conditions and its disruption by infection/inflammation promoting EMT may provide a novel pathway to preterm parturition mediated by membrane disruption.

抽象的 胎膜（羊膜）提供结构框架并执行机械和保护作用 妊娠期间的渐进性 p38 丝裂原激活蛋白激酶 (MAPK) 介导的功能。 衰老（衰老机制）发生在胎膜中，与胎儿生长相关。 由于宫腔内氧化应激（OS）增加，胎儿衰老加速。 组织引起炎症，从而促进分娩；因此，胎膜在怀孕和分娩过程中发挥着至关重要的作用； 在整个妊娠过程中，细胞膜通过自我修复来维持体内平衡。 脱落并且基质降解。这种重塑过程在细胞处产生间隙和微裂纹。 水平，目前尚不清楚膜的多能羊膜上皮细胞和间充质细胞如何修复 因为重塑对于维持膜稳态和防止不良反应至关重要。 对于妊娠结局，了解这一过程至关重要。我们已经确定羊膜损伤。 上皮细胞（AEC）迫使AEC增殖和细胞迁移以重建受损部位，这是正常的 初步数据表明，OS 和 p38 MAPK 介导的衰老会导致上皮细胞衰老。 我们还通过增加 TGFβ 的产生来促进间质转化 (EMT) 并防止组织重塑。 确定 TGFβ 具有双重功能：1）通过 p38MAPK 自身磷酸化诱导衰老 2) 诱导 EMT 转录因子以促进细胞膜和机械膜的破坏。 我们发现，平衡的组织重塑可以维持胎儿的健康。 妊娠期间膜稳态，但由于足月或反应压倒性 OS 导致 TGFβ 增加 早产时感染和炎症 (TNFα) 会导致 p38MAPK 介导的不可逆状态 衰老和 EMT 会促进膜损伤。 怀孕期间，TGFβ 介导的转变由黄体酮平衡（P4）。 2具体目标： 目标 1 — 确定 LPS（感染）和 TNFα（炎症）是否会导致 TGFβ -TAB1-p38MAPK 信号通路，导致 AEC 中的 EMT。 目标 2——确定 P4 在 LPS 和 TNFα 介导的 TGFβ 产生中的调节作用及其能力 正常情况下 TGFβ-P4 维持膜稳态及其作用 感染/炎症破坏促进 EMT 可能为早产提供新途径 由膜破坏介导。