1,25-dihydroxyvitamin D3 (1,25D) is the major steroid hormone thought to play a role in the regulation of calcium homeostasis. The goal of this project is to further our understanding of the actions of 1,25D both in vivo and at the cellular level. in vivo investigations performed in vitamin D deficient animals have revealed that this hormone plays a key role in the regulation of intestinal calcium absorption. The effects of vitamin D deficiency on other tissues, notably bone and parathyroid, are less clear, since they are not easily distinguished from the effects of hypocalcemia and hypophosphatemia. In vitro studies have been useful in clarifying the role of 1,25D, but they cannot address the protein manifestations of 1,25D deficiency, especially since normal parathyroid, osteoblast and intestinal target cell lines are not readily available. To better understand the role of both the receptor-mediated and non-genomic effects of 1,25D, a line of genetically engineered mice lacking functional 1,25D receptors has been generated. This model will permit identification of functions of 1,25D from embryogenesis to senescence, and will allow the characterization of effects of this hormone that are truly receptor-independent (if such actions occur). This investigative model of 1,25D receptor deficiency will overcome many of the problems encountered with the previous models of dietary vitamin D deficiency. The heterozygous receptor ablated mother is phenotypically normal and normocalcemic, and normal littermates will act as controls. The human disease Vitamin D Dependent Rickets Type II (VDDRII), characterized by a homozygous mutation of the 1,25D receptor, suggests that an animal model of 1,25D receptor deficiency will provide useful information. Although studies of kindreds affected by this disease have helped to clarify the receptor-dependent role of 1,25D, its low prevalence and the constraints on human investigations have limited detailed physiological and pathological studies in affected individuals. Studies of the parathyroids, bones, cartilage and intestine in 1,25D receptor ablated mice, in the setting of hypocalcemia, artificially induced normal mineral ion levels, and vitamin D deficiency will identify abnormalities that are attributable to the lack of a 1,25D receptor. Studies in receptor negative osteoblastic cells will identify actions of 1,25D that are independent of the nuclear receptor and may provide a system for studying the molecular basis of the non-genomic actions of 1,25D.
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