VITAMIN D HORMONE--FUNCTION AND MECHANISM OF ACTION

描述（改编自申请人的摘要）：本发明的目的是为了提供一种用于治疗癌症的药物组合物。 建议是为了更好地了解积极的行动， 维生素D的形式，1，25二羟维生素D3 [1，25（OH）2D 3]，在体内和 在分子水平上。 本续期申请建议继续 钙结合蛋白的功能意义，其合成 由1，25（OH）2D 3代表的最显着的体内效应之一， 1，25（OH）2D 3已知。 建议的研究包括使用钙结合蛋白-D28 k 基因敲除小鼠，并将重点关注哺乳动物钙结合蛋白-D28 k在 肾单位远端小管，调节胰岛素分泌， 防止凋亡性细胞死亡。 在上一个资助期内， 研究人员完成了钙结合蛋白对 1，25（OH）2D 3，他们发现它是适度转录的。 获得 进一步深入了解1，25（OH）2D 3作用的分子机制， 24（OH）ase基因的调节，该基因除了钙结合蛋白之外， 1，25（OH）_2D_3在肠道和肾脏中的诱导作用， 考察 1，25（OH）2D 3和其他细胞类型特异性机制 激素和信号通路协调调节24（OH）酶将是 检查，包括：1）VDR和RXR的调节; 2）对调节的影响 启动子中的区域;和3）对DNA结合转录的影响 因素 此外，与VDR相互作用的新转录因子， 介导24（OH）ase基因和骨桥蛋白基因的转录（对于 比较）将被识别和表征（候选者是YY 1，SRC-1， TAFII110）。 细胞类型和配体的基因特异性要求 将检查VDR介导的转录的独立调节。 实验也将做相关的功能意义， 24（OH）酶，使用无效突变小鼠，这将集中在拟议的作用， 24（OH）酶在维生素D代谢中的作用。 很有可能， 了解靶蛋白的功能意义，结合 随着对细胞和基因特异性相互作用的理解的增加， 1，25（OH）2D 3和VDR与其他激素和转录因子，将发挥 一个越来越重要的作用，在阐明的机制， 1，25（OH）2D 3介导其生物学效应以及异常调节如何可能 参与疾病，如骨质疏松症和 甲状旁腺功能

DESCRIPTION (Adapted from the Applicant's Abstract): The object of this proposal is to obtain a better understanding of the actions of the active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], both in vivo and at the molecular level. This renewal application proposes to continue studies related to the functional significance of calbindin, whose synthesis by 1,25(OH)2D3 represents one of the most pronounced in vivo effects of 1,25(OH)2D3 known. Proposed studies include the use of calbindin-D28k knock-out mice and will focus on effects of mammalian calbindin-D28k in the nephron's distal tubule, on modulation of insulin secretion, and on protection against apoptotic cell death. In the previous grant period, the investigators completed the characterization of calbindin's response to 1,25(OH)2D3, which they found to be modestly transcriptional. To obtain further insight into the molecular mechanism of 1,25(OH)2D3 action, regulation of the 24(OH)ase gene, the gene in addition to calbindin which is markedly induced by 1,25(OH)2D3 in the intestine and kidney, will be examined. Cell type -specific mechanisms by which 1,25(OH)2D3 and other hormones and signaling pathways coordinately regulate 24(OH)ase will be examined, including: 1) regulation of VDR and RXR; 2) effects on regulatory regions in the promoter; and 3) effects on DNA binding to transcription factors. In addition, novel transcription factors that interact with VDR to mediate transcription of the 24(OH)ase gene and the osteopontin gene (for comparison) will be identified and characterized (candidates are YY1, SRC-1, and TAFII110). Cell type and gene -specific requirements of ligand independent modulation of VDR-mediated transcription will be examined. Experiments will also be done related to the functional significance of 24(OH)ase, using null mutant mice, which will focus on the proposed role of 24(OH)ase in vitamin D metabolism. It is likely that an increased understanding of the functional significance of target proteins, combined with increased understanding of cell- and gene- specific interactions of 1,25(OH)2D3 and VDR with other hormones and transcription factors, will play an increasingly important role in the elucidation of the mechanisms by which 1,25(OH)2D3 mediates its biological effect and how aberrant regulation may be involved in diseases such as osteoporosis and perturbations of parathyroid function.