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

在英国，每年有超过70万名妇女经历怀孕，这是一个动态的、精细协调的过程，涉及母亲的全身和局部变化，以适应代谢要求高和免疫原性高的胎儿。人类妊娠疾病，如死产、低出生体重、早产和产妇糖尿病，可能是妊娠适应不良或不适当的结果，说明了这一高度管制的过程对母亲的健康及其子女的福祉的重要性。母亲在怀孕期间发生的许多内分泌和代谢变化可以直接归因于源于胎盘的信号。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只表达于一个亲代等位基因，在调节胚胎生长和胎盘支持方面发挥着重要作用。在这项研究中，我们将使用一个模型系统，在这个系统中，我们已经设计了胎盘中印记基因Phlda2表达的变化。改变Phlda2的量会改变胎盘的成分，从而使向母亲发出信号的胎盘激素的表达减少或增加。因此，怀着这些幼崽的母亲在怀孕期间要么接触到太少的荷尔蒙，要么接触到太多的荷尔蒙。众所周知，在人类怀孕期间，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，还会导致胎儿丧失。事实上，我们观察到，当母亲收到的胎盘信号太少时，我们既观察到低出生体重，也观察到一些证据表明胎儿丢失。在这项建议中，我们将简单地询问怀有Phlda2基因表达升高或缺失的幼崽的母亲是否显示出异常适应怀孕的迹象。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。此外，我们将提供关于Phlda2异常表达对母亲和她的后代的健康和福祉的影响的数据。

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.