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是至关重要的，之后后代的营养依赖于哺乳，这对母体骨骼有深刻而短暂的影响。胰岛素样生长因子(IGF)是胎盘发育和功能所必需的，可能与哺乳期母体骨骼的变化有关。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。我的研究目的是了解胎盘如何应对母体和/或发育挑战以实现成功的结局，母体骨骼如何适应怀孕和哺乳并在断奶期间恢复，以及这些胎盘和骨骼调整如何影响后代和母亲未来的健康。在接下来的五年里，这项拟议的研究将调查：*A.IGF和Papp-A2在胎盘中的作用*是否需要Papp-A2和增加的IGF水平来补偿不理想的母体饮食或损害胎盘发育的突变，将使用Papp-A2基因敲除的小鼠和对照组进行测试。*B.IGF和Papp-A2在骨骼中的作用，重点是生殖过程中的变化*母体骨骼在哺乳期失去大量骨量，然后迅速恢复，但这种恢复是如何发生的尚不清楚。在PAPP-A2基因敲除小鼠和对照组中，将在怀孕、哺乳期和哺乳期恢复期间测量IGF水平、骨转换标志和骨密度。胎盘对不理想的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的供应，从而影响母亲的骨骼。因此，我还将研究母亲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亲的骨骼产生长期影响。*C.PAPP-A2是否通过影响IGF水平以外的分子途径发挥作用*已知PAPP-A2可使一种控制IGF可获得性的蛋白质失活，但最近在鱼类中的研究表明，它也可能通过其他机制发挥作用。敲除PAPP-A2对这些途径的影响将在小鼠的胎盘和骨骼中进行调查。*这项研究将提高我们对人类和家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：胎盘如何应对怀孕期间的挑战，以实现健康的结局？哺乳后母体骨骼是如何恢复的？胎盘对挑战的反应是否会影响其分泌的荷尔蒙，从而损害母亲的骨骼？**

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?**