VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

这一修订后的竞争性更新继续了我们对维生素D受体(VDR)在 调节对活性激素1，25-二羟基维生素D3(骨化三醇)的反应。我们的双重主题 研究目的是研究维生素D受体在骨化三醇作用中的作用，并阐明抗药性的机制。 骨化三醇。我们的目标是将VDR作用的知识转化为临床应用，并改进骨化三醇 治疗作为一种抗增殖和促进分化的激素用于治疗骨质疏松症， 软骨病、癌症等。赠款有两个具体目标，都与骨化三醇的作用和机制有关 VDR阻力。初步数据表明，这两个目标都是可行的。Aim I继续我们的研究 遗传性维生素D抵抗性软骨病(HVDRR)是一种由VDR1突变引起的疾病 对骨化三醇的作用产生极端的抵抗力。次级目标将：(A)分析艾滋病毒/艾滋病的新病例；(B) 开发绕过抗性并挽救VDR缺陷的方法，以及(C)分析基因表达 突变皮肤成纤维细胞和正常皮肤成纤维细胞的图谱。AIM II是关于VDR与无毛的相互作用的研究 (HR)，最近发现的VDR的共同抑制因子。无毛基因的突变导致一种综合征 有丘疹病变的脱发(APL)与HVDRR中的脱发几乎相同。研究包括 研究VDR和HR的相互作用，重点是HVDRR突变体。次级目标包括：(A)研究 HR作为VDR抑制和调节VDR功能的作用，(B)各种HR亚型的作用，(C) VDR和HR在HVDRR中的相互作用，以及(D)在APL突变中，(E)HR导致VDR的机制 稳定，(F)调节HR和(G)寻找HR结合蛋白。我们的实验室团队有很强的技能 在这些研究中，多个合作者将添加他们的专业知识。这笔赠款是一项相当大的事业 检查VDR功能的许多方面，所有这些都是为了了解骨化三醇/VDR的作用和 荷尔蒙抵抗。其重要意义将是开发和使用含有VDR自然突变的细胞 而HR是研究骨化三醇分步作用机制的理想试剂。通过 为了阐明细胞如何对骨化三醇的作用产生抵抗力，我们希望制定策略来克服 对患有HVDRR或APL的儿童的耐药性和改进的治疗方法以及寻找方法 增强骨化三醇的作用，可能治疗骨质疏松症、癌症和牛皮癣等疾病。

This revised competitive renewal continues our research into the role of the vitamin D receptor (VDR) in regulating the response to the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol). The dual themes of our research are to study the role of the VDR in calcitriol action and to elucidate mechanisms of resistance to calcitriol. Our goals are to translate knowledge of VDR action to clinical applications and improve calcitriol therapy as an anti-proliferative and pro-differentiating hormone for use in the treatment of osteoporosis, rickets, cancer, etc. The grant has two Specific Aims, both related to calcitriol action and mechanisms of VDR resistance. Preliminary data indicate that both of the Aims are feasible. Aim I continues our study of children with Hereditary Vitamin D Resistant Rickets (HVDRR) a disease due to mutations in theVDR1 causing extreme resistance to the action of calcitriol. Sub-Aims will: (a) analyze new cases of HVDRR, (b) develop methods to bypass the resistance and rescue the VDR defect, and (c) analyze the gene expression profile in mutant and normal skin fibroblasts. Aim II is a study of the interaction of the VDR with Hairless (HR), a recently recognized co-repressor of the VDR. Mutations in the hairless gene cause a syndrome of alopecia with papular lesions (APL) that is virtually identical to the alopecia in HVDRR. Studies include an examination of VDR and HR interactions with emphasis on HVDRR mutants. Sub-Aims include (a) studies of the role of HR as a VDR suppressor and regulator of VDR function, (b) the role of various isoforms of HR, (c) VDR and HR interactions in HVDRR, and (d) in APL mutants, (e) mechanisms by which HR leads to VDR stabilization, (f) regulation of HR and (g) search for HR binding proteins. Our lab group has substantial skills in these studies and multiple collaborators will add their expertise. The grant is a substantial undertaking examining many aspects of VDR function, all directed towards understanding calcitriol/VDR action and hormone resistance. The significance will be to develop and employ cells harboring natural mutations in VDR and HR as ideal reagents that allow interogation of the step by step mechanism of action of calcitriol. By elucidating how cells become resistant to the action of calcitriol we hope to develop strategies to overcome the resistance and develop improved treatment for children with HVDRR or APL as well as to find ways to enhance calcitriol action to potentially treat diseases such as osteoporosis, cancer and psoriasis.