Grant: Project Grant

Background: During pregnancy, mothers double the efficiency of absorbing calcium and phosphate from their intestines to meet the needs of their fetuses. Conversely, during breastfeeding, much of the calcium and phosphate in mother's milk comes from their skeletons and not their diet. The placenta pumps needed minerals to fetuses, whereas newborns use their intestines to absorb minerals. These adaptations are programmed to occur but how they are regulated is poorly understood. We know that the hormones that regulate mineral and bone physiology in non-pregnant adults are not required during pregnancy, breastfeeding, or by developing fetuses. There must be novel hormones or factors that regulate these adaptations. If we can identify these hormones, they might become treatments for mineral and bone disorders at any life stage. Animal data are especially important for understanding the roles of hormones, since human studies are usually not possible during pregnancy and fetal development. Goals: to clarify the roles of parathyroid hormone-related protein (PTHrP) and calcitriol (active vitamin D) in regulating mineral and bone physiology in mother and fetuses. Hypotheses: PTHrP derived from the placenta is a key regulator of fetal mineral homeostasis including calcitriol production; maternally produced PTHrP regulates maternal mineral physiology and calcitriol production during pregnancy; treatments that reduce PTHrP-stimulated calcitriol synthesis or increase its degradation will improve outcomes in a genetic disorder that causes critically high blood calcium during pregnancy. Outcomes: We will improve our understanding of how mineral and bone physiology is regulated during pregnancy and fetal development; to see the extent to which maternal hormones regulate the fetus & placenta and vice versa; and to gain insights from the animal model as to how best to treat the human condition that causes high blood calcium during pregnancy.