ROLE OF 1,25 DIHYDROXYVITAMIN D DURING FETAL LIFE

许多早产儿在出生后的前24小时内发生低钙血症。 生活 其中，20%的人可能会有随后的骨骼 脱矿（骨质减少、佝偻病、长骨骨折）。 的 潜在的机制是未知的，但可能涉及异常的维生素D 新陈代谢. 本建议旨在帮助澄清 维生素D的激素形式，即1，25二羟维生素D （1，25（OH）2D）在胎儿宫内生活期间的矿物质经济中的作用。 以下具体问题将得到解决：1）什么是 胎儿肾脏和胎盘对胎儿发育的相对贡献 在宫内生活期间循环1，25（OH）2D浓度？ 2)是 正常的胎儿循环1，25（OH）2D浓度， 子宫内矿物质代谢 3)胎盘和胎儿骨骼 对1，25（OH）2D在胎儿期的作用有反应的靶器官？ 在我们研究的第一阶段，单胎羊胎儿将在 妊娠110天（第145期），以确定1，25（OH）2D合成 胎儿-胎盘单位的容量。 这将通过测量 胎儿1，25（OH）2D的产生和代谢清除率， 使用体内胎盘合成速率的测量 胎盘灌注技术 正常妊娠相关变化 还将评估血清矿物质和钙调节激素 纵向从110天到138天妊娠时，正常胎盘 将测定矿物质转移和胎儿矿物质利用率。 在我们研究的第二阶段，我们将使用双侧肾切除的胎儿， 确定胎儿肾脏1，25（OH）2D合成能力丧失的影响 对胎儿血清1，25（OH）2D和矿物质浓度、胎盘矿物质 转移和胎儿矿物质利用率。 基于我们之前 研究表明，胎儿肾切除会导致胎儿低钙血症， 高磷酸盐血症和降低的胎儿血清1，25（OH）2D浓度。 我们 假设这些变化是由1，25（OH）2D介导的 胎盘矿物质转移和正常骨矿化的破坏， 将通过外源性1，25（OH）2D治疗在很大程度上得到纠正。 这些综合研究将为功能性 1，25（OH）2D在胎儿生命中的作用，因为它涉及到 早产儿低钙血症和骨脱矿。

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.