The roles of PAPP-A2 and IGF signaling in reproduction

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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?**