VITAMIN D RESISTANCE AND RELATED DISORDERS

维生素 D 抵抗和相关疾病

• 批准号: 5202064
• 负责人: J BARSONY
• 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/5202064
• 关键词: 1,25 dihydroxycholecalciferol; alopecia; cyclic GMP; fibroblasts; gene mutation; human subject; human therapy evaluation; human tissue; metabolism disorder chemotherapy; nutrition disorder chemotherapy; osteomalacia; skeletal disorder chemotherapy; skin pharmacology; vitamin D resistant rickets

With recognition that vitamin D is the precursor for 1,25-dihy- droxyvitamin D, it has become possible to characterize defects in the target actions of 1,25-dihydroxyvitamin 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 all 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 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 (103 minutes) rise of cyclic GMP in response to 1,25 (OH) 2 D3 and that certain receptor mutations compromise many receptor functions but allow another function ot be retained normally. This establishes that 1,25 (OH) 2D receptors couple to different responses by distinct mechanisms. With the development of a new, pharmacologically relevant fluorescent 1,25 (OH) 2D, it became possible to study vitamin D receptor activation; in living cells and recognize abnormalities in vitamin D receptor translocation from the cytoplasm to the nucleus.

认识到维生素D是1，25-二羟基- 羟维生素D，它已成为可能的特点缺陷，在 1，25-二羟维生素D的靶向作用。 我们展示了一个广泛的 对1，25（OH）2D遗传抗性表现谱， 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。 来自所有受试者的皮肤成纤维细胞， 对1，25（OH）2D的遗传性耐药性在这种情况下显示异常 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）突变的细胞 2D效应通路可用于探讨钙化醇的作用机制 行动上 它们已被用于确定1，25（OH）2D受体 介导环鸟苷酸的快速（103分钟）上升， 1，25（OH）2 D3，某些受体突变会损害许多 受体功能，但允许另一种功能不能正常保留。 这确定了1，25（OH）2D受体与不同的 不同机制的反应。 随着一种新的、 相关的荧光1，25（OH）2D， 研究维生素D受体的激活;在活细胞中， 维生素D受体从细胞质易位到 原子核