VITAMIN D RESISTANCE AND RELATED DISORDERS

维生素 D 抵抗和相关疾病

• 批准号: 3855305
• 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/3855305
• 关键词: 1,25 dihydroxycholecalciferol; N hydroxylation; alopecia; child (0-11); cyclic GMP; drug resistance; fibroblasts; gene mutation; hormone regulation /control mechanism; human subject; inborn metabolism disorder; orphan disease /drug; osteomalacia; receptor coupling; rickets; steroid biosynthesis; steroid hormone metabolism; steroid hormone receptor; tissue /cell culture; vitamin D resistant rickets; vitamin biosynthesis; vitamin metabolism

With recognition that vitamin D is the precursor for l,25-dihydroxyvitamin D, it has become possible to characterize defects in the activation (l-hydroxylation) of vitamin D and defects in the target action of activated (l,25-dihydroxy)vitamin D. We have demonstrated a broad spectrum of manifestations of hereditary resistance to l,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 all subjects with hereditary resistance to l,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 effector pathway can be used to explore mechanisms of calciferol action. They have been used to establish that the 1,25(OH)2D receptor mediates 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L的前体，25-二羟基维生素 D，已经有可能表征活化过程中的缺陷 维生素D的(L-羟化)及其靶向作用缺陷 激活(L，25-二羟基)维生素D。我们已经证明了一种广谱的维生素D 关于对L的遗传抗性的表现，25(OH)2D 婴儿软骨病脱发，对骨化醇无肠道反应 至成人起病的骨软化症，肠道对HIGH反应满意 剂量为骨化醇，且无表皮异常。本综合征 通常是由于维生素D受体基因突变所致。 所有对L具有遗传性抵抗的受试者皮肤成纤维细胞，25(OH)2D 显示在这个效应器系统中的异常，以及许多离散的缺陷 这条途径的步骤已经在这些细胞中被识别出来。单元格带有 1，25(OH)2D效应通路的突变可用于探索 骨化醇的作用机制。它们被用来证明 1，25(OH)2D受体介导极快速(1-3分钟)的 环GMP对1，25(OH)2D3和某些受体突变的响应 损害了许多受体功能，但允许另一种功能 正常保留。这证实了1，25(OH)2D受体与 通过不同的机制做出不同的反应。