Copper deprivation results in perinatal death, serious fetal malformations, and dysynchrony in development, which is related in part to abnormal maturation of connective tissues and defective oxidative defense mechanisms. Diabetes during pregnancy also results in a high frequency of serious fetal malformations in humans and experimental animals. In addition to abnormal fuel metabolism, diabetes can cause perturbations in copper (Cu) metabolism, abnormalities in connective tissue maturation and defective oxidant defense. Consequently, a focus of this proposal is to examine mechanistically Cu deprivation from a developmental perspective. We also will contribute information on the extent to which Cu-related events are important to selected pathologies that are observed in diabetes. There are four specific aims.
Specific aim one is to determine how maternal Cu deprivation alters embryonic and/or fetal uptake/retention of Cu.
Specific aim two is to relate changes in maternal and fetal hepatic uptake and distribution of Cu with changes in diet and/or endocrine status.
Specific aim three is to establish developmental priorities in Cu utilization for superoxide dismutase, lysyl oxidase and ceruloplasmin.
Specific aim four is to characterize how diet and the diabetic state alters extracellular matrix deposition in heart and major vessels in the fetus, neonate and adult. The work involves well established animal models, immunological and molecular biological techniques. If in the above studies it is shown that diabetes has long lasting effects on Cu metabolism and the development of the offspring, this will suggest the need for new approaches in the management of pregnant diabetic women and their offspring. In addition, the results from these studies will have broad applications in developmental biology related to the teratogenicity of an important essential nutrient, i.e., copper.
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