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

点击翻译按钮获取中文摘要

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.