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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，要么是作为补充剂通过口腔摄入的。维生素D然后需要由肾脏激活（通过酶1-羟化酶，1-OH酶）来帮助身体通过肠道吸收钙，并帮助骨骼硬化（矿化）。在某些情况下，如衰老和肾脏疾病，肾脏变得不太能够激活维生素D，这可能导致骨骼变弱。Streeten博士观察到，在为骨质疏松症和其他疾病的患者看病的过程中，有些人似乎无法充分激活维生素D，即使他们很年轻，肾脏健康。在这种情况下，为了弥补缺乏活性维生素D，激素从甲状旁腺（4腺体在颈部，有助于控制钙平衡），甲状旁腺激素，分泌过多进入血液。过量的甲状旁腺激素会导致骨质流失。这些患者疑似部分1-OH酶缺乏。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。Streeten博士计划研究8名疑似部分1-OH酶缺乏症的患者和8名对照。我们计划用3种方法研究8例患者和8例对照组中1-OH-酶的功能：（1）通过静脉（IV）输注PTH（对酶的天然刺激物）刺激1-OH-酶。我们将给予Forteo（合成PTH，FDA批准用于骨质疏松症）IV，剂量为先前研究人员使用的剂量，12 pmol/kg/hr，持续8小时。在该剂量下未观察到副作用和1，25-D的最大刺激。Dr. Streeten已从FDA获得在本研究中使用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-OH酶的基因序列。我们希望在患者中发现与对照组相比的序列差异。(3)取一个小的4 mm皮肤穿刺活检组织，我们将从中测量1-羟化酶的活性。虽然循环1，25-D的主要来源是肾脏1-羟化酶，但皮肤中也存在这种酶。皮肤酶分析将由波士顿大学的Michael Holick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