The roles of PAPP-A2 and IGF signaling in reproduction

生殖需要几个生理系统的协调和对不同挑战的适当反应。在胎盘哺乳动物中，胎盘在妊娠期间为胎儿提供营养和氧气至关重要，之后后代的营养取决于哺乳，这对母体骨骼有深刻但短暂的影响。胰岛素样生长因子（IGF）是胎盘发育和功能所必需的，并且可能参与哺乳期间发生的母体骨骼变化。妊娠相关血浆蛋白-A2（PAPP-A2）是一种知之甚少的蛋白质，可能在生殖过程中调节IGF水平方面很重要。我的研究的目的是了解胎盘如何应对母体和/或发育的挑战，以取得成功的结果，母体骨骼如何调整怀孕和哺乳，并在断奶期间恢复，以及这些胎盘和骨骼的调整如何影响后代和母亲未来的健康。在未来五年内，拟议的研究将调查： A. IGF和PAPP-A2在胎盘中的作用 是否需要PAPP-A2和增加的IGF水平来补偿次优的母体饮食或损害胎盘发育的突变，将使用PAPP-A2敲除小鼠和对照进行测试。 B。IGF和PAPP-A2在骨骼中的作用，重点关注生殖过程中的变化 母亲的骨骼在哺乳期会失去大量的骨量，然后迅速恢复，但不知道这种恢复是如何发生的。将在妊娠、哺乳和哺乳恢复期间测量PAPP-A2敲除小鼠和对照小鼠的IGF水平、骨转换标志物和骨矿物质密度。胎盘对次优饮食或损害其发育的突变的反应可能会影响母亲血液中IGF的可用性，从而影响母亲的骨骼。因此，我也将研究母体的饮食或胎盘缺陷是否会影响生殖过程中的骨骼调整，以及生殖是否会对母体骨骼产生长期影响。 C. PAPP-A2是否通过影响IGF水平以外的分子途径起作用 已知PAPP-A2是一种控制IGF可用性的蛋白质，但最近在鱼类中的研究表明，它也可能通过其他机制起作用。将在小鼠胎盘和骨中研究敲除PAPP-A2对这些途径的影响。 这项研究将提高我们对人类和驯养动物健康生殖的基本理解，因此对所有加拿大人都有意义。它将解决以下问题：胎盘如何应对妊娠期间的挑战，以实现健康的结局？哺乳后母体骨骼如何恢复？胎盘对挑战的反应是否会影响其分泌的激素，从而损害母体骨骼？

Reproduction requires the coordination of several physiological systems and appropriate responses to diverse challenges. In placental mammals, the placenta is crucial for supplying the fetus with nutrients and oxygen during gestation, after which offspring nutrition depends on lactation, which has profound but transient effects on the maternal skeleton. Insulin-like growth factor (IGF) is required for the development and function of the placenta, and is likely involved in the changes in the maternal skeleton that take place during lactation. Pregnancy-associated plasma protein-A2 (PAPP-A2) is a poorly understood protein that may be important in regulating IGF levels during reproduction. The objectives of my research are to understand how the placenta responds to maternal and/or developmental challenges to achieve a successful outcome, how the maternal skeleton adjusts to pregnancy and lactation and recovers during weaning, and how these placental and skeletal adjustments affect the future health of the offspring and mother. Over the next five years, the proposed research will investigate: A. The roles of IGF and PAPP-A2 in the placenta Whether PAPP-A2 and increased IGF levels are required to compensate for suboptimal maternal diet or for mutations that impair placental development will be tested using PAPP-A2 knock-out mice and controls. B. The roles of IGF and PAPP-A2 in bone, focusing on changes through reproduction The maternal skeleton loses substantial bone mass during lactation and then recovers quickly, yet it is not known how this recovery occurs. IGF levels, markers of bone turnover and bone mineral density will be measured during pregnancy, lactation and recovery from lactation in PAPP-A2 knock-out mice and controls. Placental responses to suboptimal diet or to mutations that impair its development might affect IGF availability in the mother's blood and so affect the maternal skeleton. Therefore, I will also examine whether maternal diet or placental defects affect skeletal adjustments during reproduction, and whether reproduction has long-term effects on the maternal skeleton. C. Whether PAPP-A2 acts through molecular pathways other than affecting IGF levels PAPP-A2 is known to inactivate a protein that controls IGF availability, but recent work in fish suggests that it may also act through other mechanisms. The effect of knocking out PAPP-A2 on these pathways will be investigated in placenta and bone in mice. This research will improve our basic understanding of healthy reproduction in humans and domesticated animals and so is of relevance to all Canadians. It will address questions such as: How does the placenta respond to challenges during pregnancy to achieve a healthy outcome? How does the maternal skeleton recover after lactation? Do placental responses to challenges affect the hormones that it secretes in a way that compromises the maternal skeleton?