THE ROLE OF 1,25 DIHYDROXYVITAMIN D DURING FETAL LIFE

1,25 二羟基维生素 D 在胎儿生命中的作用

• 批准号: 3157621
• 负责人: RICHARDUS ROSS
• 金额: $ 11.04万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1988-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3157621
• 关键词: 1,25 dihydroxycholecalciferol; atomic absorption spectrometry; bone metabolism disorder; embryo /fetus; high performance liquid chromatography; hypocalcemia; kidney function; kidney metabolism; longitudinal animal study; nephrectomy; nutrition related tag; parathyroid hormones; pregnancy circulation; premature infant animal; radioimmunoassay; respiratory gas analyzer; scintillation spectrometry; vitamin biosynthesis; vitamin metabolism; vitamin therapy

Many premature infants develop hypocalcemia during the first 24 hours of life. Of these, twenty percent may have subsequent skeletal demineralization (osteopenia, rickets, long bone fractures). The underlying mechanisms are unknown but may involve abnormal vitamin D metabolism. The present proposal is designed to help clarify the role of the hormonal form of vitamin D, namely, 1,25 dihydroxyvitamin D (1,25(OH)2D) in the mineral economy of the fetus during intrauterine life. The following specific questions will be addressed: 1) What are the relative contributions of the fetal kidney and the placenta to fetal circulating 1,25(OH)2D concentrations during intrauterine life? 2) Are normal fetal circulating 1,25(OH)2D concentrations necessary for normal intrauterine mineral metabolism? 3) Are the placenta and fetal bone responsive target organs for the action of 1,25(OH)2D during fetal life? In phase I of our study, singleton sheep fetuses will be instrumented at 110 days of gestation (term 145) to determine the 1,25(OH)2D synthetic capacity of the fetal-placental unit. This will be done by measurement of the fetal Production and Metabolic Clearance Rates of 1,25(OH)2D and by measurement of the in vivo placental synthesis rate using an in vivo placental perfusion technique. Normal gestationally related changes in serum minerals and calcium regulating hormones will also be assessed longitudinally from 110 days to 138 days of gestation when normal placental mineral transfer and fetal mineral utilization rates will be determined. In phase II of our study, we will use bilaterally nephrectomized fetuses to determine the impact of loss of fetal renal 1,25(OH)2D synthetic capacity on fetal serum 1,25(OH)2D and mineral concentrations, placental mineral transfer and fetal mineral utilization rates. Based on our previous studies, fetal nephrectomy will result in fetal hypocalcemia, hyperphosphatemia and reduced fetal serum 1,25(OH)2D concentrations. We hypothesize that these changes result from reduced 1,25(OH)2D-mediated placental mineral transfer and disruption of normal bone mineralization and will be largely corrected by treatment with exogenous 1,25(OH)2D therapy. These combined studies will provide valuable insight into the functional role of 1,25(OH)2D during fetal life, as it relates to the etiology of hypocalcemia and bone demineralization in prematurity.

许多早产儿在出生后的头24小时内出现低钙血症 生活。在这些人中，20%可能有后来的骨骼 脱矿(骨量减少、软骨病、长骨骨折)。这个 潜在的机制尚不清楚，但可能涉及异常的维生素D 新陈代谢。本提案的目的是帮助澄清 维生素D的激素形式，即1，25二羟基维生素D (1，25(OH)2D)在胎儿宫内生活中的矿物质经济。 将解决以下具体问题：1)什么是 胎儿肾脏和胎盘对胎儿的相对贡献 宫内循环中的1，25(OH)2D浓度？2) 正常胎儿循环中正常所需的1，25(OH)2D浓度 宫内矿物质代谢？3)胎盘和胎骨 胎儿时期1，25(OH)2D作用的反应靶器官？ 在我们研究的第一阶段，独生羊胚胎将在 妊娠110天(第145期)测定1，25(OH)2D合成 胎儿-胎盘单位的容量。这将通过测量以下各项来完成 1，25(OH)2D和1，25(OH)2D对胎儿的产生量和代谢清除率的影响 体内胎盘合成率的测定 胎盘灌注法。正常妊娠相关的变化 还将评估血清矿物质和钙调节激素。 胎盘正常时，纵向妊娠110天至138天 将测定矿物质转移率和胎儿矿物质利用率。 在我们的第二阶段研究中，我们将使用双侧肾切除的胎儿来 测定胎儿肾脏1，25(OH)2D合成能力丧失的影响 胎儿血清1，25(OH)2D和矿物质浓度、胎盘矿物质 转移率和胎儿矿物质利用率。基于我们之前的 研究表明，胎儿肾切除会导致胎儿低钙血症， 高磷血症和胎儿血清1，25(OH)2D浓度降低。我们 假设这些变化是由1，25(OH)2D介导的减少引起的 胎盘矿物质转移和破坏正常的骨矿化和 将通过外源性1，25(OH)2D治疗在很大程度上得到纠正。 这些联合研究将提供有价值的洞察功能 1，25(OH)2D在胎儿生命中的作用 早产儿低钙血症和骨脱矿。