Placental hormones and adaptability of feto-maternal physiology

胎盘激素与母胎生理适应性

• 批准号: RGPIN-2016-04063
• 负责人: Cross, James
• 金额: $ 2.99万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688339
• 关键词: Placental; hormones; adaptability; feto; maternal

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**

胎盘哺乳动物的生活史涉及子宫内母亲和幼崽之间复杂的相互作用。胎盘运输营养物质和气体，但母亲在怀孕期间经历了新陈代谢、大脑和行为以及血液系统的深刻适应，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，但该系统的复杂性只有在现代基因组学中才变得清晰——胎盘表达了数十种激素，但它们正在迅速进化。人类胎盘表达80个多肽激素基因，其中4个是由生长激素（GH）基因的复制而产生的胎盘特异性基因，而其他76个基因反映了胎盘特异性激素基因的增强子或启动子的进化，否则在脑、肾和脂肪中表达。小鼠胎盘表达40个多肽激素基因，其中22个是通过泌乳素（Prl）基因的复制产生的（生长激素基因在小鼠中没有复制）。在绵羊中，GH和Prl基因都有复制，而在狗中这两个基因都没有复制。尽管基因组存在差异，但人类、老鼠、羊和狗都具有母性生理适应性。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驱动代谢、行为和心血管适应。为了支持这一观点，小鼠的功能得失实验表明，Phlda2基因调节胎盘中内分泌细胞的数量，并且Phlda2的表达差异与小鼠、人类和牛的胎儿生长速率有关。胎儿生长是一项重要特征，因为出生时体重过低的动物或人类有较高的新生儿死亡风险、发育迟缓风险以及晚年患心血管和代谢疾病的风险（成人健康和疾病的发育起源）。***我项目的长期目标是确定胎盘激素的进化及其对妊娠结局的贡献。作为关键背景，我们培养了缺乏胎盘特异性催乳素相关激素（PPRH）大家族的小鼠，发现这些小鼠的表型与人类胎盘中表达的激素的功能一致，这些激素调节母体对妊娠的代谢、心血管和行为适应。我们的数据显示，这些激素对胎儿生长很重要，但也保护母亲在怀孕期间的健康，它们的表达适应母亲饮食的变化。***未来5年的具体目标是：***1)确定妊娠激素网络并与物种间妊娠的相关性***2)将特定胎盘激素归因于母体对妊娠的适应***3)确定胎盘激素缺乏小鼠对母体应激的适应能力***4)描述IUGR和非啮齿动物营养不良时胎盘激素的变化**