CHARACTERIZATION OF SUSPECTED PARTIAL 25-HYDROXYVITAMIN D-1-ALPHA HYDROXYLASE DY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 维生素D对骨骼健康非常重要。维生素D要么是在阳光照射后在皮肤中形成的，要么是作为补充剂由口腔摄入。然后维生素D需要被肾脏激活(被1-羟基酶，1-OH-ase激活)，以帮助身体通过肠道吸收钙，并帮助骨骼变得硬化(矿化)。在某些情况下，如衰老和肾脏疾病，肾脏激活维生素D的能力变得较弱，这可能导致骨骼虚弱。在为患有骨质疏松症和其他疾病的患者看病的过程中，斯特里顿博士观察到，一些人似乎无法充分激活维生素D，即使他们还很年轻，肾脏也很健康。在这种情况下，为了弥补活性维生素D的缺乏，来自甲状旁腺(颈部帮助控制钙平衡的4个腺体)的激素-甲状旁腺激素被过度分泌到血液中。过量的甲状旁腺激素会导致骨质流失。这些患者怀疑为部分1-羟基酶缺乏症。他们升高的甲状旁腺激素(PTH)可以通过给予他们活性维生素D(1，25-二羟基维生素D，1，25-D，称为骨化三醇)来纠正。斯特里顿博士计划对8名疑似1-羟基酶缺乏症的患者和8名对照组进行研究。我们计划用3种方法研究8例患者和8名对照的1-羟基酶的功能：(1)静脉输注甲状旁腺素(PTH)来刺激1-羟基酶，PTH是酶的自然刺激物。我们将给Forteo(合成甲状旁腺素，FDA批准用于骨质疏松症)静脉注射之前研究人员使用的剂量，12 pmol/kg/hr，持续8小时。在此剂量下，1，25-D未见副作用和最大刺激性。Streeten博士已经从FDA获得了在这项研究中使用Forteo的IND(#76,579)。(2)我们将从每个参与者身上抽取血液，从中提取DNA，以确定1-羟基酶的基因序列。我们希望发现与对照组相比，患者的序列有所不同。(3)取小面积4 mm皮肤穿孔活检，测定1-羟基酶活性。虽然1，25-D循环的主要来源是肾脏的1-羟基酶，但这种酶也存在于皮肤中。皮肤酶分析将由波士顿大学的迈克尔·霍利克博士完成

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vitamin D is very important for bone health. Vitamin D is either formed in the skin after sunlight shines on it or is taken in by mouth as a supplement. Vitamin D then needs to be activated by the kidneys (by the enzyme 1-hydroxylase, 1-OH-ase) to do its job in helping the body to absorb calcium through the intestinal tract, and helping the bone to become hardened (mineralized). In some situations, such as aging and in kidney diseases, the kidneys become less able to activate vitamin D and this can lead to weakened bones. Dr. Streeten has observed, during the course of seeing patients for osteoporosis and other conditions, that some people appear to be unable to adequately activate vitamin D even though they are young and have healthy kidneys. In this situation, to compensate for the lack of activated vitamin D, the hormone from the parathyroid glands (4 glands in the neck that help to control calcium balance), parathyroid hormone, is secreted excessively into the blood. Excessive parathyroid hormone can cause bone loss. These patients have suspected partial 1-OH-ase deficiency. Their elevated parathyroid hormone (PTH) can be corrected by giving them activated vitamin D (1,25-dihydroxyvitamin D, 1,25-D, called calcitriol). Dr. Streeten plans to study 8 patients with suspected partial 1-OH-ase deficiency and 8 controls. We plan to study the function of the 1-OH-ase enzyme in the 8 patients and 8 controls in 3 ways: (1) Stimulating the 1-OH-ase enzyme by giving an intravenous (IV) infusion of PTH, the natural stimulus to the enzyme. We will give Forteo (synthetic PTH, FDA approved for osteoporosis) IV in a dose used by previous researchers, 12 pmol/kg/hr over 8 hours. No side effects and maximal stimulation of 1,25-D have been seen at this dose. Dr. Streeten has obtained an IND from the FDA for use of Forteo in this study (#76,579). (2) We will take blood from each participant, from which we will extract DNA to determine the sequence of the gene for 1-OH-ase. We hope to find a difference in the sequence in the patients compared to controls. (3) A small 4 mm skin punch biopsy will be taken from which we will measure the activity of the 1-hydroxylase enzyme. Although the main source of circulating 1,25-D is by the kidney 1-hydroxylase enxyme, the enzyme is also present in skin. The skin enzyme analysis will be done by Dr. Michael Holick at Boston University