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.

肥胖症，II型糖尿病及其相关并发症是我们卫生系统永久增加的挑战。更重要的是，越来越多的儿童和青少年超重，患有慢性疾病。解决真正途径的主要根源的一种方法是针对早期生活，采用发育起源方法来预防疾病。孕妇过量的妊娠体重增加和怀孕期间的孕产妇超重是儿童后代肥胖和代谢综合征的最强预测指标。有人提出，母亲肥胖的代谢后果可能会导致HPA轴的破坏，这是全天由皮质醇水平升高所进行的，胎儿过度暴露于母体皮质醇作为一种将肥胖与肥胖与慢性疾病联系起来的途径。斑点可能在皮质醇相关的编程效果中起重要作用。我们对内源性皮质醇和/或与MODP相关的内源性皮质醇和/或HPA干扰如何影响胎儿和斑点发育的理解始于糖皮质激素受体（GR）及其同工型。皮质醇诱导的表观基因组学修饰在GR和/或下游信号传导途径的特定启动子区域中具有高/甲基化的表观遗传学修饰，例如位置皮质溶质屏障和/或斑点葡萄糖转运蛋白，这些葡萄糖转运蛋白转运蛋白被激活或反射在升高的Cortisol中，最终导致了较高的位置GRSSINED GRSSENAL SENSITIVES和功能。我们假设性别特异性皮质醇的敏感性受GR分布，表达和/或相互作用的调节，作为翻译刺激GR与其他斑点GR同工型，并且材料MODP改变了这些关系。斑点GR同工型的不同簇特异性与位置功能，胎儿和新生儿结局参数相关。因此，我们从MODP妊娠的正常体重和斑点对人斑点进行研究，以性别和胎龄为特定的特异性鉴定以及斑点Gr alpha vs.其他GR-相关型的定位，物理功能的相关评估，HPA，HPA，HPA，葡萄糖运输，斑点皮质固体的抗性）以及ftf ftfels and ftsort和ftsort and ftsort and ftsort and ftsort sopt and cort and corts and cort and col表观基因组GR和其他候选促进剂的变化是性别特异性斑点皮质醇耐药性和胎儿MAL分机的可能机制。敏感技术和定量技术（例如焦磷酸测序和实时PCR）的组合可以评估组织和性别特异性方式的表观遗传变化。在确定后代长期健康方面，对置换式介导的信号通路的增强对在高危人群设计介入策略的努力至关重要，并且有可能使我们能够在未来的研究中识别生物标志物和目标进行干预试验。