VITAMIN D RESISTANCE AND RELATED DISORDERS

维生素 D 抵抗和相关疾病

• 批准号: 3918196
• 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/3918196
• 关键词: 1,25 dihydroxycholecalciferol; calcium; child (0-11); dosage; drug resistance; fibroblasts; guanosine monophosphate; hormone receptor; human subject; orphan disease /drug; osteocytes; osteomalacia; renal rickets; rickets; steroid biosynthesis; steroid hormone metabolism; tissue /cell culture; vitamin D deficiency; vitamin biosynthesis; vitamin metabolism

The calciferols were the first class of hormonally active steroids to oe discovered and also the first for which subjects with hormone resistance could be identified. 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(0H)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. Alopecia is found only in cases with the most severe grades of resistance to 1,25(0H)2D. This finding implicates the 1,25(0H)2D receptor, for the first time, in normal function of a tissue (hair follicle) outside the classical target in duodenal mucosa. A similar disorder has been recognized in new world monkeys. Cultured skin fibroblasts display many components of the 1,25(0H)2D effector system. Skin fibroblasts from all subjects with hereditary resistance to 1,25(0H)2D display abnormalities in this effector system, and defects in many discrete steps of this pathway have been identified with these cells. Other cells, such as bone cells, lymphocytes, and parathyroid cells can also be used to evalute actions of 1,25(0H)2D in vitro. Cells with mutations in the 1,25(0H)2D effector pathway can be used to explore mechanisms of calciferol action. They have been used to establish that the 1,25(0H)2D receptor mediates an extremely rapid (1-3 minutes) rise of cyclic GMP in response to 1,25(0H)2D3.

钙化醇是第一类具有生理活性的甾体化合物 也是第一个被发现的， 可以识别阻力。 认识到维生素D 是1，25-二羟维生素D的前体，它已经成为 可以表征激活中的缺陷（1- 羟基化）的维生素D和缺陷的目标行动， 活性（1，25-二羟基）维生素D。 我们展示了一个广泛的 对1，25（0 H）2D的遗传抗性表现谱 从婴儿佝偻病伴有脱发和没有肠道 钙化醇对成人骨软化症的反应 对高剂量钙化醇的满意肠道反应， 没有表皮异常 脱发只出现在 对1.25（OH）2D具有最严重的抗性等级。 这 这一发现首次涉及1，25（OH）2D受体， 正常功能的组织（毛囊）以外的经典 靶向于十二指肠粘膜。 一种类似的疾病已经被发现 在新大陆的猴子身上 培养的皮肤成纤维细胞显示出许多 1，25（0 H）2D效应器系统的组件。 皮肤成纤维细胞 来自所有对1，25（0 H）2D显示具有遗传抗性的受试者 这个效应器系统的异常，以及许多离散系统的缺陷， 已经用这些细胞鉴定了该途径的步骤。 其他 细胞如骨细胞、淋巴细胞和甲状旁腺细胞可 也可用于体外评价1，25（OH）2D的作用。 细胞与 1，25（OH）2D效应通路中的突变可用于探索 钙化醇的作用机制。 它们被用来建立 1，25（OH）2D受体介导了一个非常快速的（1-3 分钟）响应于1，25（OH）2D 3的环GMP升高。