Grant: Project Grant

Adaptations during reproduction ensure adequate delivery of calcium and phosphate. During pregnancy, intestinal calcium and phosphate absorption double, whereas during lactation, the skeleton is preferentially resorbed. After weaning, intestinal calcium and phosphate absorption and bone formation increase, and the maternal skeleton is restored. During fetal development, the placenta actively pumps minerals to facilitate skeletal growth and mineralization, while in the neonate, the intestines use passive mechanisms to upregulate intestinal mineral absorption. The known calcium and phosphate regulating hormones are not required for these adaptations to be invoked. Overall significance: understanding normal mineral and skeletal physiology during these time periods, and the pathophysiology of relevant disorders, will increase our ability to optimally treat these conditions. We may also identify novel regulators, which in turn may lead to new approaches to treating disorders of mineral and bone metabolism. Our goals of this proposal are to clarify the role of calcitriol (active vitamin D) in the mother during reproductive cycles and in the fetus and early neonate. Our hypotheses are that a) maternal calcitriol rather than offspring calcitriol influences fetal and early neonatal development; b) catabolism of calcitriol has important effects on mineral homeostasis during reproductive cycles as well as fetal and neonatal development; and c) factors other than calcitriol upregulate intestinal calcium and phosphate absorption during pregnancy, lactation and post-weaning. Four specific aims address these goals and hypotheses, by assessing: 1. whether maternal calcitriol deficiency has lasting effects on neonatal skeletal metabolism 2. how loss of catabolism of calcitriol alters maternal or fetal mineral homeostasis 3. whether Pdia3 mediates actions of calcitriol on the placenta 4. to identify regulators of intestinal mineral absorption during pregnancy and lactation