Maternal Overweight During Pregnancy (MODP) and perinatal programming – effects on placental function and the role of placental glucocorticoid receptors

母亲妊娠期超重 (MODP) 和围产期规划 â 对胎盘功能的影响和胎盘糖皮质激素受体的作用

• 批准号: 428871172
• 负责人: Privatdozent Dr. Thorsten Braun
• 金额: --
• 依托单位: Klinik für Geburtsmedizin (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428871172?language=en
• 关键词: Maternal; Overweight; During; Pregnancy; MODP

Obesity, type II diabetes and its associated complications are a permanently increasing challenge for our health system. Even more important, a growing number of children and adolescents are overweight and suffer from chronic diseases. One way to address a major root of the causative pathway is to target early life, applying a developmental origins approach to disease prevention. Maternal excessive gestational weight gain and maternal overweight during pregnancy (MODP) are the strongest predictors of offspring obesity and metabolic syndrome in children. It has been proposed that the metabolic consequences of maternal obesity may contribute to HPA axis disruption, accompanied by elevated cortisol levels throughout the day, with fetal overexposure to maternal cortisol as a pathway linking obesity to chronic disease later in life. The placenta may play an important role in the cortisol-associated programming effects. Our understanding of how endogenous cortisol and/or HPA-disruption associated with MODP influences fetal and placental development begins with the glucocorticoid receptor (GR) and its isoforms. Cortisol-induced epigenomic modifications with hyper-/hypomethylation in specific promoter regions of GR and/or down-stream signaling pathways, such as the placental cortisol barrier and/or placental glucose transporters that are activated or repressed in the presence of elevated cortisol, finally contribute to altered placental GR sensitivity and function. We hypothesize that sex-specific cortisol sensitivity is regulated by GR distribution, expression and/or interaction of GRα as transduction stimulating GR vs. other placental GR isoforms and that maternal MODP changes these relationships. Different clusters of placental GR isoforms correlate sex-specifically with placental function, fetal and neonatal outcome parameters. We therefore propose studies in human placentas from normal weight and placentas from MODP pregnancies with the objective of sex- and gestational-age specific identification and localization of placental GR alpha vs. other GR-isoforms, the correlative evaluation of the physiological function (HPA, glucose transport, placental cortisol resistance) and impact of the GR isoforms for fetal development, and cortisol/MODP-induced epigenomic GR and other candidates-promotor changes as a possible mechanism of gender-specific placental cortisol resistance and fetal mal-programming. The combination of sensitive and quantitative technologies (e.g. pyrosequencing and Real-Time PCR) could enable assessment of epigenetic changes in a tissue and sex-specific manner. An enhanced appreciation of placental-mediated signaling pathways in determining long-term health in offspring will be crucial in the efforts to design interventional strategies in at-risk populations and will potentially allow us to identify biomarkers and targets for intervention trials in future studies.

肥胖、II型糖尿病及其相关并发症对我们的卫生系统来说是一个永久性的日益增长的挑战。更重要的是，越来越多的儿童和青少年超重并患有慢性病。解决致病途径的主要根源的一种方法是针对早期生活，应用发育起源方法来预防疾病。孕妇妊娠超重和孕期超重(MODP)是儿童后代肥胖和代谢综合征的最强预测因子。有人提出，母体肥胖的代谢后果可能导致HPA轴紊乱，伴随着全天皮质醇水平的升高，胎儿过度暴露于母体皮质醇是将肥胖与晚年慢性病联系起来的一条途径。胎盘可能在皮质醇相关的编程效应中发挥重要作用。我们对与MODP相关的内源性皮质醇和/或HPA干扰如何影响胎儿和胎盘发育的理解始于糖皮质激素受体(GR)及其亚型。皮质醇诱导的表观基因组修饰在GR的特定启动子区和/或下游信号通路，如胎盘皮质醇屏障和/或胎盘葡萄糖转运体，在皮质醇升高的情况下被激活或抑制，最终导致胎盘GR敏感性和功能的改变。我们假设性别特异性皮质醇敏感性受GR的分布、表达和/或作为转导刺激性GR的GRα与其他胎盘GR亚型的相互作用的调节，并且母体MODP改变了这些关系。不同的胎盘GR亚型簇与性别相关--特别是与胎盘功能、胎儿和新生儿结局参数相关。因此，我们建议对正常体重的胎盘和MODP妊娠的胎盘进行研究，目的是对胎盘GRα与其他GR亚型进行性别和胎龄特异性鉴定和定位，相关生理功能(HPA、葡萄糖运输、胎盘皮质醇抵抗)和GR亚型对胎儿发育的影响，以及皮质醇/MODP诱导的表观GR和其他候选启动子的变化，作为性别特异性胎盘皮质醇抵抗和胎儿编程的可能机制。将敏感和定量技术(例如焦磷酸测序和实时聚合酶链式反应)结合起来，能够以组织和性别特有的方式评估表观遗传学变化。加强对胎盘介导的信号通路在确定子代长期健康方面的认识，将在高危人群中设计干预策略的努力中至关重要，并可能使我们能够在未来的研究中识别干预试验的生物标记物和靶点。