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 胎儿机制（羊膜处理）提供结构框架并进行机械和保护 怀孕期间的功能。进行性p38有丝分裂原激活的蛋白激酶（MAPK）介导的 胎儿膜发生感应（衰老机制）。它与胎儿的生长相关，是 由于插入腔中的氧化应激（OS）增加而在期限加速。胎儿衰老 组织会引起炎症，可以促进劳动；因此，膜在怀孕和 分娩。在整个妊娠期间，膜通过在细胞为时修复自身来维持稳态 棚子，矩阵降解。此重塑过程会产生差距和微裂缝。在细胞 水平，目前尚不清楚膜的多能羊膜上皮和间质细胞如何修复 损坏的站点。由于重塑对于维持膜体内稳态和预防逆境至关重要 怀孕结果，了解这一过程至关重要。我们已经确定了羊膜的伤害 上皮细胞（AEC）迫使AEC增殖和细胞迁移到重建受伤的部位，这是正常的 生理反应。试验数据表明OS-和p38 MAPK介导的感应引起上皮 间充质转变（EMT），并通过增加TGFβ的产生来防止组织重塑。我们也是 确定TGFβ扮演双重函数：1）通过自磷酸化p38mapk诱导感应 2）诱导EMT转录因子，以促进细胞和机械膜破坏。这些 孕酮（P4）逆转了影响。我们假设平衡组织重塑保持胎儿 怀孕期间的膜稳态，但由于OS在学期或响应时，TGFβ增加了 在早产下感染和注射（TNFα）导致p38mapk介导的不可逆状态 感应和EMT可以促进膜损伤。此外，我们假设在 怀孕，TGFβ介导的过渡通过孕激素平衡（P4）。我们将使用 2特定目的： 目标1-确定LPS（感染）和TNFα（炎症）是否会引起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产生及其能力中的调节作用 减少EMT。在正常条件下，TGFβ-P4维持膜稳态及其 感染/炎症促进EMT的破坏可能为早产提供新的途径 由膜破坏介导。