ACTIONS OF 1,25-DIHYDROXYVITAMIN D3 IN CHRONIC RENAL FAILURE

这项建议继续进行中的研究有关的改变维生素 慢性肾功能衰竭（CRF）患者甲状旁腺激素（PTH）水平的变化。 具体而言，将研究两个方面：1）维生素的变化 D受体的表达和作用（2）肾组织中D受体的表达和调节 和肾外1-羟化酶。 维生素D受体（VDR）水平在甲状旁腺中降低， CRF患者和动物。血清1，25（OH）_2D_3（a 刺激VDR水平）和增加CRF中PTH（VDR抑制剂 可能是导致VDR水平低的原因。 拟议的研究将 检查1，25-（OH）2D 3和PTH在VDR调节中的作用， 对CRF大鼠的甲状旁腺和肠道进行了观察。 将分析VDR 用于1，25-（OH）2D 3和DNA结合亲和力，并通过1，25- （OH）2D 3结合并通过Western和北方印迹分析。 培养 甲状旁腺细胞将用于检查1，25- （OH）2D 3、PTH等因素对VDR水平及其DNA结合的影响 亲和力 此外，将在尿毒症患者中进行研究， 确定循环1，25-（OH）2D 3本身的浓度是否具有 抑制PTH的作用。 我们还将确定 对新开始透析的患者给予1，25-（OH）2D 3 改变继发性甲状旁腺功能亢进的自然病程。 不同程度的维生素D缺乏与CRF相关。 尽管 高PTH，肾1 α-羟化酶的刺激物，残余的酶， 不能补偿1，25-（OH）2D 3的产生。 然而，非常低的 无肾患者的1，25-（OH）2D 3水平可显著升高 25（OH）D3处理后，表明底物可用性的作用 肾外1.25-（OH）2D 3产生。 对25（OH）D的亲和力 肝和外周巨噬细胞的肾外1 α-羟化酶， 尿毒症的症状 我们将检查表达式之间的关联 肾外1-α-羟化酶和血清1，25-（OH）2D 3降低 随着肾衰竭的进展 自2001年以来， 肾外1 α-羟化酶与肾内1 α-羟化酶明显不同。 酶，我们将研究肾外1，25-（OH）2D 3的调节 生产作为一种潜在的治疗工具，以防止改变， 钙稳态与骨化三醇缺乏的关系 肾衰竭

This proposal continues ongoing studies related to alterations in vitamin D and parathyroid hormone (PTH) in chronic renal failure (CRF). Specifically, two areas will be investigated: 1) ALTERATIONS IN VITAMIN D RECEPTOR EXPRESSION AND ACTION 2) EXPRESSION AND REGULATION OF RENAL AND EXTRA-RENAL 1-HYDROXYLASE. Vitamin D receptor (VDR) levels are decreased in parathyroid glands of patients and animals with CRF. The decrease serum 1,25(OH)2D3 (a stimulator of VDR levels) and increase PTH (a suppressor of VDR) in CRF are likely causes of the low VDR levels. The proposed studies will examine the roles of 1,25-(OH)2D3 and PTH in the regulation of VDR in the parathyroid glands and intestine of rats with CRF. VDR will be analyzed for 1,25-(OH)2D3 and DNA binding affinity, and quantitated by 1,25- (OH)2D3 binding and by Western and Northern blot analysis. Cultured parathyroid cells will be used to examine the direct effects of 1,25- (OH)2D3, PTH, and other factors on the levels of VDR and its DNA binding affinity. In addition, studies will be performed in uremic patients to determine if the concentration of circulating 1,25-(OH)2D3 per se has a role in the suppression of PTH. We will also determine if the administration of 1,25-(OH)2D3 to patients newly starting dialysis modifies the natural history of secondary hyperparathyroidism. Various degrees of vitamin D deficiency are associated with CRF. Despite high PTH, a stimulator of renal 1alpha-hdroxylase, the remnant enzyme is unable to compensate 1,25-(OH)2D3 production. However the very low levels of 1,25-(OH)2D3 in anephric patients can rise dramatically following 25(OH)D3 treatment suggesting a role for substrate availability in extrarenal 1.25-(OH)2D3 generation. The affinity for 25(OH)D of the extrarenal 1alpha-hydroxylases of liver and peripheral macrophages is reduced in uremia. We will examine the associated between the expression of extrarenal 1-alpha-hydroxylase and the reduction in serum 1,25-(OH)2D3 with the progression of renal failure. Since the regulation of extrarenal 1 alpha-hydroxylase differs markedly from that of the renal enzyme, we will examine the modulation of extrarenal 1,25-(OH)2D3 production as a potential therapeutic tool to prevent the alterations in calcium homeostasis association with calcitriol deficiency in severe renal failure.