VITAMIN D RESISTANCE AND RELATED DISORDERS

维生素 D 抵抗和相关疾病

• 批准号: 3776680
• 负责人: S J MARX
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3776680
• 关键词: 1,25 dihydroxycholecalciferol; N hydroxylation; alopecia; cyclic GMP; drug resistance; fibroblasts; gene mutation; hormone regulation /control mechanism; human subject; human tissue; inborn metabolism disorder; nutrition related tag; orphan disease /drug; osteomalacia; receptor coupling; rickets; steroid biosynthesis; steroid hormone metabolism; steroid hormone receptor; tissue /cell culture; vitamin D; vitamin D resistant rickets; vitamin biosynthesis; vitamin metabolism

With recognition that vitamin D is the precursor for 1.25- dihydroxyvitamin D, it has become possible to characterize defects in the activation (1-hydroxylation) of vitamin D and defects in the target action of activated (1,25-dihydroxy) vitamin D. We have demonstrated a broad spectrum of manifestations of hereditary resistance to 1,25 (OH)2D ranging from infantile rickets with alopecia and no intestinal response to calciferols to adult onset osteomalacia with satisfactory intestinal response to high doses of calciferols and with no epidermal abnormalities. This syndrome usually results from a mutation in the gene for the vitamin D receptor. Skin fibroblasts from al subjects with hereditary resistance to 1,25(OH)2D display abnormalities in this effector system, and defects in many discrete steps of this pathway have been identified with these cells. Cells with mutations in the 1,25(OH)2D receptor mediated an extremely rapid (1-3 minutes) rise of cyclic GMP in response to 1,25(OH)2D3 and that certain receptor mutations compromise many receptor functions but allow another function to be retained normally. This establishes that 1,25(OH)2D receptors couple to different responses by distinct mechanisms.

认识到维生素D是1.25-的前体 二羟维生素D，它已成为可能的特点缺陷，在 维生素D的活化（1-羟基化）和靶点缺陷 活性（1，25-二羟基）维生素D的作用。 我们展示了一个 对1，25（OH）2D的遗传性抗性的广谱表现 从婴儿佝偻病伴有脱发和无肠道反应 钙化醇治疗成人骨软化症， 对高剂量钙化醇的反应， 异常 这种综合症通常是由基因突变引起的 维生素D受体。 所有受试者的皮肤成纤维细胞 对1，25（OH）2D的遗传性抗性显示这种异常， 效应器系统，以及该途径的许多离散步骤中的缺陷， 与这些细胞有关。 1，25（OH）2D突变的细胞 受体介导的环鸟苷酸（cGMP）的快速（1-3分钟）上升， 对1，25（OH）2D 3的反应和某些受体突变会损害 许多受体功能，但允许保留另一种功能 正常情况下 这确定了1，25（OH）2D受体与不同的 不同机制的反应。