Placental hormones and adaptability of feto-maternal physiology

胎盘哺乳动物的生活史涉及到母亲和她的幼崽在子宫内的复杂相互作用。胎盘运输营养和气体，但母亲在怀孕期间在新陈代谢、大脑和行为以及血液系统方面经历了深刻的适应，以支持胎儿的生长。来自胎盘的激素通常被视为胎儿和母亲之间资源分配的调节器，但这个系统的复杂性直到现代基因组学才变得清晰起来--胎盘表达了数十种激素，但它们正在迅速进化。小鼠胎盘表达40个多肽激素基因，其中22个是通过复制催乳素(PRL)基因而产生的(GH基因在小鼠中不复制)。在绵羊身上，生长激素和催乳素基因都是复制的，而在狗身上，这两个基因都不是复制的。尽管基因组存在差异，但人类、小鼠、绵羊和狗都有共同的母体生理适应。我们的假设是，胎盘激素直接或通过与其他内分泌器官的相互作用推动新陈代谢、行为和心血管适应。为了支持这一点，小鼠的功能丧失和获得实验表明，Phlda2基因调节胎盘中的内分泌细胞数量，并且在小鼠、人和牛中，Phlda2的表达差异与胎儿生长速度有关。胎儿生长是一个重要的特征，因为出生体重低的动物或人类新生儿死亡、发育迟缓以及日后患心血管和代谢性疾病的风险较高(成人健康和疾病的发育起源)。*我的计划的长期目标是确定胎盘激素的演变及其对妊娠结局的贡献。我们的数据显示，这些激素对胎儿生长很重要，但也保护了母亲怀孕期间的健康，它们的表达适应了母亲饮食的变化。*未来5年的具体目标是：*1)定义妊娠激素网络并与跨物种的妊娠相关*2)将特定的胎盘激素归因于母体对怀孕的适应*3)确定胎盘激素缺乏的小鼠适应母体应激的能力*4)描述IUGR中胎盘激素的变化和非啮齿动物物种的营养不良**

The life history of placental mammals involves a complex interplay between mother and her young within the uterus. The placenta transports nutrients and gases but the mother undergoes profound adaptations in her metabolic, brain and behavior, and blood systems during gestation to support fetal growth. Hormones from the placenta are often viewed as regulators in the allocation of resources between fetus and mother, but the complexity of the system is only becoming clear from modern genomics - there are dozens of hormones expressed by the placenta but they are rapidly evolving. The human placenta expresses 80 polypeptide hormone genes, four of which are placenta-specific arising from duplication of the Growth Hormone (GH) gene while the other 76 genes reflect evolution of placenta-specific enhancers or promoters in canonical hormone genes otherwise expressed in brain, kidney and fat. The mouse placenta expresses 40 polypeptide hormone genes, 22 of which arose through duplication of the Prolactin (Prl) gene (the GH gene is not duplicated in mice). In sheep, both the GH and Prl genes are duplicated whereas neither gene is duplicated in dogs. Despite the genome differences, humans, mice, sheep and dogs share maternal physiological adaptations. Our hypothesis is that placental hormones drive metabolic, behavioral and cardiovascular adaptations directly or through interaction with other endocrine organs. In support of this, loss and gain of function experiments in mice have shown that the Phlda2 gene regulates endocrine cell number in the placenta, and Phlda2 expression differences are associated with fetal growth rate in mice, humans and cattle. Fetal growth is an important trait since animals or humans born with low birth weight have higher risks of neonatal death, developmental delay and risk of cardiovascular and metabolic disease later in life (developmental origins of adult health and disease). ***The long-term objective of my program is to define the evolution of placental hormones and their contributions to pregnancy outcome. As key background, we developed mice lacking a large family of placenta-specific Prolactin-related hormones (PPRH) and found that the mice have phenotypes consistent with functions of hormones that are expressed in the human placenta, regulating maternal metabolic, cardiovascular and behavioral adaptations to pregnancy. Our data show these hormones are important for fetal growth but also protect the health of the mother during pregnancy and their expression adapts to changes in maternal diet. ***The specific aims for the next 5 years are to:***1) Define pregnancy hormone network and correlate with gestation across species***2) Attribute specific placental hormones to maternal adaptations to pregnancy***3) Determine the ability of placental hormone-deficient mice to adapt to maternal stress***4) Describe placental hormone changes in IUGR and poor nutrition in non-rodent species**