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、二型糖尿病及其相关并发症对我们的卫生系统来说是一个日益严峻的挑战，更重要的是，越来越多的儿童和青少年超重并患有慢性疾病，解决其主要根源的方法之一是。以早期生命为目标，采用发育起源方法来预防疾病。 母亲妊娠期体重过度增加和母亲妊娠期间超重（MODP）是后代肥胖和代谢综合征的最强预测因子。肥胖可能会导致HPA 轴破坏，伴随着全天皮质醇水平升高，胎儿过度接触母体皮质醇是导致肥胖与以后生活中慢性疾病的一个途径。胎盘可能在我们对皮质醇相关编程效应的理解中发挥着重要作用。与 MODP 相关的内源性皮质醇和/或 HPA 破坏影响胎儿和胎盘发育，始于糖皮质激素受体 (GR) 及其异构体诱导的表观基因组修饰。 GR 特定启动子区域和/或下游信号通路的高甲基化/低甲基化，例如在皮质醇升高的情况下激活或抑制的胎盘皮质醇屏障和/或胎盘葡萄糖转运蛋白，最终有助于胎盘 GR 敏感性和我们探索了性别特异性皮质醇敏感性受 GRα 的 GR 分布、表达和/或相互作用的调节，作为刺激 GR 与其他胎盘 GR 亚型的转导，并且母体 MODP 改变了这些关系。因此，我们建议对正常体重的人类胎盘和 MODP 妊娠的胎盘进行研究，目的是对性别和胎龄进行特异性识别和定位。胎盘 GR α 与其他 GR 亚型的比较，生理功能（HPA、葡萄糖转运、胎盘皮质醇抵抗）的相关评估以及 GR 亚型的影响胎儿发育、皮质醇/MODP 诱导的表观基因组 GR 和其他候选启动子变化作为性别特异性胎盘皮质醇抵抗和胎儿错误编程的可能机制。敏感和定量技术的结合（例如焦磷酸测序和实时 PCR）。可以以组织和性别特异性的方式评估表观遗传变化，增强对胎盘介导的信号通路在确定后代长期健康方面的认识对于设计干预策略至关重要。高危人群，并有可能使我们能够在未来的研究中确定干预试验的生物标志物和目标。