DISORDERS OF MINERAL METABOLISM IN CHILDREN

儿童矿物质代谢紊乱

• 批准号: 2825254
• 负责人: THOMAS O CARPENTER
• 金额: $ 9.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2825254
• 关键词: 1,25 dihydroxycholecalciferol; 25 hydroxycholecalciferol; adolescence (12-20); alkaline phosphatase; blood chemistry; bone metabolism; clinical research; clinical trials; collagen; combination chemotherapy; dosage; hormone regulation /control mechanism; human middle age (35-64); human subject; human therapy evaluation; hyperparathyroidism; kidney function; liver function; metabolism disorder chemotherapy; middle childhood (6-11); osteocalcin; parathyroid hormones; vitamin D resistant rickets; vitamin therapy; young adult human (21-34)

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.

该申请描述了卡彭特博士的职业和临床研究 成就。 他的简历和正在进行的项目的清单描述了 候选人大力投资于临床的重点方向 在儿童矿物质代谢领域进行的调查。 他的 致力于培训学生和研究员，以及他在耶鲁大学的主要角色 在这方面，强调了。 Carpenter博士的直接职业目标 专注于两个项目：1）使用24,25（OH）2d3在处理 儿童骨骼疾病； 2）隔离和纯化 磷酸盐（PI）浪费来自PI-患有PI-pi-poi的肿瘤的物质 浪费致癌性骨质乳酸。 这些项目的第一个是在卡彭特博士的最初的 24,25（OH）2d3的试验改善了次磷酸血症的骨骼疾病 瑞克（XLH）。 该研究确定轻度甲状旁腺功能亢进为 XLH的频繁特征及其用24,25（OH）2d3进行校正。 一个 随后的试点研究表明，自主的成功抑制 4例接受甲状旁腺切除术的4名XLH患者的甲状旁腺功能亢进。 因此，评估24,25（OH）2d3的疗效和安全性的对照试验 在XLH中的自主性甲状旁腺功能亢进症的管理中 此应用程序中的主要项目。 甲状旁腺的昼夜概况 在随机分组之前将获得激素（PTH）分泌 安慰剂或24,25（OH）2d3，与标准疗法一起给予。 在2 将对pth月度间隔进行采样，剂量为24,25（OH）2d3将是 如果PTH水平未随着初始剂量水平降低而增加。 监测其他矿物质水平和PTH生物活性将是 执行。 一年后，重复昼夜PTH轮廓将是 获得。 次要项目，鉴定磷 致癌性骨质乳腺癌肿瘤中的因子涉及系列 具有差异选择性的色谱法（例如，离子交换，尺寸 排除，反向相HPLC）。 原材料是条件培养基 来自永生的肿瘤细胞。 通过抑制评估生物活性 肾上皮细胞中的PI转运测定法。 这个项目将 提供关键的新信息以了解正常PI XLH的稳态和病理生理学。 其他相关研究 还描述了项目。 如应用程序所述，耶鲁大学的资源非常适合 进行临床研究，包括NIH支持的一般 临床研究中心。 此外，长期存在 与内科部门的合作 骨科提供了丰富的智力环境和批判性的环境 群众兴趣。