Achieving a successful pregnancy: Epigenetic regulation of fetal-maternal signaling

英国每年有超过700，000名女性经历怀孕，这是一个动态、精心协调的过程，涉及母亲的全身和局部变化，以适应代谢要求和免疫原性的胎儿。人类妊娠疾病，如死胎、低出生体重、早产和母体糖尿病，可能是对妊娠适应不良或不适当的结果，这说明了这一高度调节的过程对母亲健康及其子女福祉的重要性。许多内分泌和代谢的变化，发生在母亲怀孕期间可以直接归因于来自胎盘的信号。我们正在研究印记基因在调节从胎盘到母亲的这些信号中的作用。印记基因在哺乳动物中仅由一个亲本等位基因表达，在调节胚胎生长和胎盘支持方面发挥重要作用。在这项研究中，我们将使用一个模型系统，在该系统中，我们设计了胎盘中印记基因Phlda2表达的变化。改变Phlda2的量会改变胎盘的组成，从而减少或增加向母亲发出信号的胎盘激素的表达。因此，携带这些幼崽的母亲在怀孕期间会接触到太少或太多的这些激素。众所周知，在人类妊娠中，母体血清中这些激素的异常水平与低出生体重有关，在某些情况下，与胎儿丢失有关。事实上，我们观察到低出生体重和一些证据胎儿损失时，我们的母亲收到太少的胎盘信号。在这个提议中，我们将简单地询问携带Phlda2表达升高或表达缺失的幼崽的母亲是否显示出对妊娠的异常适应的指标。这项研究值得注意的是，我们将能够证明胎儿中的印记基因可以在怀孕期间操纵母亲的生理机能。此外，我们将提供Phlda2异常表达对母亲及其后代的健康和福祉的后果的数据。

Pregnancy, which is experienced by over 700,000 women per year in the United Kingdom, is a dynamic, exquisitely coordinated process involving systemic and local changes in the mother to accommodate the metabolically demanding and immunogenic fetus. Disorders of human pregnancy, such as stillbirth, low birth weight, preterm birth and maternal diabetes may occur as a consequence of poor or inappropriate adaptation to pregnancy illustrating the importance of this highly regulated process, both for the health of the mother and for the well being of her children. Many of the endocrine and metabolic changes that occur in the mother during pregnancy can be directly attributed to signals originating from the placenta. We are investigating the role of an imprinted gene in regulating these signals from the placenta to the mother. Imprinted genes, which are expressed in mammals from only one parental allele, play an important role in regulating embryonic growth and placental support. In this study, we will use a model system in which we have engineered changes in the expression of the imprinted gene, Phlda2, in the placenta. Changing the amount of Phlda2 alters the composition of the placenta such that there is either decreased or increased expression of placental hormones that signal to the mother. Consequently mothers carrying these pups will be exposed to either too little or too much of these hormones during pregnancy. It is well known that in human pregnancies, abnormal levels of these hormones in maternal serum are associated with low birth weight and, in some case, fetal loss. Indeed, we observe both low birth weight and some evidence fetal loss when our mothers receive too little of the placental signals. In this proposal, we will simply ask whether mothers carrying pups with elevated expression or loss of expression of Phlda2 show indicators of abnormal adaptation to pregnancy. What is remarkable about this study is that we will be able to show that an imprinted gene in the fetus can manipulate the mother's physiology during pregnancy. Additionally, we will provide data on the consequences of aberrant expression of Phlda2 on the health and well being of both the mother and her offspring.