VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

这项修订后的竞争性更新继续我们对维生素D受体（VDR）在 调节对活性激素1，25-二羟维生素D3（骨化三醇）的反应。我们的双重主题 研究的目的是研究维生素D受体在骨化三醇作用中的作用，并阐明耐药机制。 骨化三醇我们的目标是将VDR作用的知识转化为临床应用， 作为用于治疗骨质疏松症的抗增殖和促分化激素的治疗， 该补助金有两个具体目标，都与骨化三醇的作用和机制有关， VDR电阻。初步数据表明，这两个目标都是可行的。目的一继续研究 患有遗传性维生素D抵抗性佝偻病（HVDRR）的儿童，这是一种由于VDR1突变引起的疾病 导致对骨化三醇作用的极端抵抗。子目标将：（a）分析HVDRR的新病例，（B） 开发绕过抗性和挽救VDR缺陷的方法，以及（c）分析基因表达 在突变和正常皮肤成纤维细胞中的分布。目的二是研究VDR与Hairless的相互作用 (HR)，最近认识到的VDR的共阻遏物。无毛基因的突变会导致 具有丘疹性病变的脱发（APL），其与HVDRR中的脱发几乎相同。研究包括 检查VDR和HR相互作用，重点是HVDRR突变体。次级目标包括：（a）研究 HR作为VDR抑制剂和VDR功能调节剂的作用，（B）HR的各种同种型的作用，（c） HVDRR中VDR和HR的相互作用，以及（d）APL突变体中，（e）HR导致VDR的机制 稳定化，（f）调节HR和（g）寻找HR结合蛋白。我们的实验组有着丰富的技能 在这些研究中，多个合作者将增加他们的专业知识。这笔赠款是一项重大的承诺 检查VDR功能的许多方面，所有这些都是为了理解骨化三醇/VDR的作用， 激素抵抗其意义将是开发和使用携带VDR天然突变的细胞 和HR作为理想的试剂，允许逐步探究骨化三醇的作用机制。通过 阐明细胞如何对骨化三醇的作用产生抗性，我们希望开发克服的策略， 为HVDRR或APL儿童开发更好的治疗方法， 增强骨化三醇的作用以潜在地治疗诸如骨质疏松症、癌症和牛皮癣的疾病。

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.