Molecular Alterations of Thyroid Hormone Metabolism in the Human Placenta due to Maternal Obesity

据估计，目前德国孕妇的肥胖患病率约为30%，并呈上升趋势。众所周知，肥胖妇女患妊娠期糖尿病和先兆子痫以及围产期并发症的风险增加。此外，孕妇在怀孕期间的饮食和体重对胎儿的发育和健康产生负面影响（畸形、早产、死产、大于胎龄儿（LGA）的风险较高）。研究表明，LGA新生儿在婴儿期更容易患上代谢综合征，在以后的生活中沿着肥胖、葡萄糖耐量受损和胰岛素抵抗。为了防止由于母亲肥胖对下一代造成的健康风险，提高我们对决定所观察到的胎儿过度生长和母亲肥胖之间的关联的分子机制的理解是一个令人感兴趣的问题。Kjersti Aagaards研究小组已经证明，母体甲状腺激素以及胎儿下丘脑-垂体-甲状腺轴在调节胎儿生长方面起着重要作用。对日本猕猴的研究表明，肥胖母鼠和高脂肪饮食母鼠的后代fT 4值显著降低。与这些发现相一致的是，已经描述了碘甲状腺原氨酸脱碘酶基因（DIO）的失调、α和β-甲状腺素受体的表观遗传修饰沿着它们的辅激活物的更高表达。基于上述结果，我们假设母体高脂饮食和母体肥胖同样改变了人胎盘中的信号通路，以及胎儿下丘脑-垂体-甲状腺轴的变化。胎盘通过某些机制（转运蛋白、脱碘酶）控制母体激素向胎儿的传递。这些机制的改变将是我研究项目的中心点。该项目的第一步包括利用qRT-PCR和免疫组织化学测定人胎盘中甲状腺激素转运蛋白、结合蛋白、受体和DIO基因的数量和定位。其次，我们将从人胎盘中分离细胞滋养层细胞，并分析胎盘组织对甲状腺激素暴露的分子反应。为此，将进行细胞滋养层培养，并进行基因表达分析和ChIP测序。使用这种方法，我们将能够分析改变后的基因表达的细胞滋养层处理后的文化与三碘甲腺原氨酸（T3）。此外，我们希望获得与对照组相比，肥胖孕妇中哪些基因被激活的证据。最后，我们想了解T3处理的影响下，启动子的占据如何改变。

The prevalence of obesity in pregnant women in Germany is estimated to be approximately 30% today - with a rising tendency. It is well known that obese women are at increased risk of developing gestational diabetes and preeclampsia as well as perinatal complications. In addition, maternal diet and body weight during pregnancy influence the fetal development and health negatively (higher risk for malformations, preterm, stillbirth, large for gestational age (LGA)). Studies indicate that LGA newborns develop metabolic syndrome during infancy more often, coming along with obesity, impaired glucose tolerance and insulin resistance later in life. In order to prevent health risks due to maternal obesity in the next generation it is a matter of interest to improve our understanding of the molecular mechanism that determine the observed association between excessive fetal growth and maternal obesity. Kjersti Aagaards research group has demonstrated that maternal thyroid hormones as well as the fetal hypothalamic-pituitary-thyroid axis play a major role in the regulation of fetal growth. Studies with Japanese macaques revealed that offspring of obese dams and dams with a high fat diet had significantly lower fT4 values. In coherence with these findings, a dysregulation of iodothyronin-deiodinase-genes (DIO), epigenetic modifications of alpha- and beta-thyroid-hormone-receptors along with a higher expression of their coactivators have been described. Based on the outlined results, we assume that maternal high fat diet and maternal obesity similarly alters signaling pathways in the human placenta, in addition to changes in the fetal hypothalamic-pituitary-thyroid axis. The placenta controls the passage of maternal hormones to the fetus with the help of certain mechanisms (transport proteins, deiodinases). Alterations in these mechanisms will be at the center point of my research project. The first step of the project comprises the determination of quantity and localization of thyroid hormone transporters, binding proteins, receptors and DIO-genes in the human placenta utilizing qRT-PCR and immunohistochemistry. Secondly we will isolate cytotrophoblasts from human placenta and analyze the molecular reaction of placenta tissue to thyroid hormones exposure ex vivo. For this purpose cytotrophoblast cultures will be spread and gene expression analyses as well as ChIP sequencing will be conducted. Using this approach we will be enabled to analyze the altered gene expression in cytotrophoblasts after treating the culture with triiodothyronine (T3). In addition, we hope to acquire evidence which genes are activated in obese pregnant women in comparison to a control group. Finally, we would like to obtain insight in how the occupation of promoters alters under the influence of T3 treatment.