This application describes Dr. Carpenter's career and clinical research accomplishments. His CV and list of ongoing projects describe a candidate strongly invested in the focused direction of clinical investigation in the field of mineral metabolism in children. His commitment to training students and fellows, and his major role at Yale in this regard is emphasized. Dr. Carpenter's immediate career goals focus on two projects: 1) the use of 24,25(OH)2D3 in the treatment of childhood bone disease; and 2) the isolation and purification of a phosphate (Pi) wasting substance from tumors from children with Pi- wasting oncogenic osteomalacia. The first of these projects arose following Dr. Carpenter's initial trial of 24,25(OH)2D3 to improve skeletal disease in hypophosphatemic rickets (XLH). The study identified mild hyperparathyroidism as a frequent feature of XLH, and its correction with 24,25(OH)2D3. A subsequent pilot study indicated successful suppression of autonomous hyperparathyroidism in 4 XLH patients considered for parathyroidectomy. Thus, a controlled trial evaluating efficacy and safety of 24,25(OH)2D3 in the management of autonomous hyperparathyroidism in XLH comprises the primary project in this application. Diurnal profiles of parathyroid hormone (PTH) secretion will be obtained prior to randomization to placebo or 24,25(OH)2D3, given in concert with standard therapy. At 2 month intervals PTH will be sampled, and doses of 24,25(OH)2D3 will be increased if PTH levels have not decreased with initial dose levels. Monitoring of other mineral levels and PTH bioactivity will be performed. After one year, repeat diurnal PTH profiles will be obtained. The secondary project, identification of a phosphaturic factor(s) in oncogenic osteomalacia tumors, involves serial chromatography with differential selectivity (e.g., ion exchange, size exclusion, reverse phase HPLC). Source material is conditioned medium from immortalized tumor cells. Bioactivity is assessed by inhibition of Pi transport assay in renal epithelial cells. This project will provide critical new information for understanding normal Pi homeostasis, and pathophysiology of XLH. Other related research projects are also described. Resources at Yale, as described in the application, are ideal for performing clinical research, including the NIH-supported General Clinical Research Centers. Furthermore, the long-standing collaborations with the Departments of Internal Medicine and Orthopaedics provide for a rich intellectual environment, and critical mass of interest.
