Our proposed studies are designed to investigate the role of abnormal vitamin D metabolism in the pathogenesis of X-linked hypophosphatemic rickets (XLH) and the effectiveness and complications of long-term calcitriol and phosphate therapy in patients with this disease. Abnormalities of vitamin D metabolism will be examined in affected humans and in Hyp-mice, the murine homologue of the disorder. Investigations in mutant mice will include efforts to further characterize the abnormality of 1,25(OH)2D biosynthesis evident in these animals (and in patients with XLH). In addition, we will employ a variety of approaches to explore if the aberrant regulation of 1,25(OH)2D production is secondary to alterations of the hormonal/metabolic milieu in the diseased animals. Using renal transplantation (Hyp to normal; normal to Hyp-mouse) and assay of 25(OH)D-1 and 24R-Hydroxylase activities in resultant isografts, we will explore the linkage between the primary genetic error in XLH, abnormal renal phosphate transport, and the aberrantly regulated enzyme activity. Further, employing measurements of enzyme hydroxylase activities in non-renal tissues and in renal tubule suspensions in vitro, we will establish whether the abnormality of 1,25(OH)2D production occurs in all enzyme bearing tissues and if it is due to abnormal phosphate transport. In humans we will determine whether defective regulation of 1,25(OH)2D production is similar to that in mutant mice. Studies in the Hyp-mice will also include efforts to investigate whether the bone mineralization defect is a consequence of abnormal vitamin D metabolism and hypophosphatemia or is due in part to an intrinsic derangement of the osseous structure. In these investigations we will employ renal transplantations to determine if presence of the bone lesion is invariably associated with the characteristic renal dysfunction exhibited in Hyp-mice. Evaluation of the therapeutic strategy for XLH will place emphasis on determining the spectrum of complications attendant upon long-term therapy and the impact of these events on patient care. In addition, we will test alternative therapeutic strategies to that already developed if complications are severely limiting. Collectively, the planned studies will provide new information regarding the regulation of vitamin D metabolism. In addition, important perspective concerning the pathogenesis of X-linked hypophosphatemic rickets (and related vitamin D resistant diseases) will be obtained and effective low-risk therapeutic strategies for these disorders defined.
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