VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

描述（由申请人提供）：此修订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1，25-二羟基维生素D3（骨化三醇）的反应中的作用的研究。我们的研究的双重主题是研究维生素D受体在骨化三醇作用中的作用，并阐明骨化三醇耐药的机制。我们的目标是将VDR作用的知识转化为临床应用，并改善骨化三醇治疗作为一种抗增殖和促分化激素，用于治疗骨质疏松症，佝偻病，癌症等。初步数据表明，这两个目标都是可行的。目的我继续我们的研究儿童遗传性维生素D抵抗性佝偻病（HVDRR）的疾病，由于突变的VDR 1造成极端抵抗的行动骨化三醇。次级目标将：（a）分析HVDRR的新病例，（B）开发绕过抗性和挽救VDR缺陷的方法，和（c）分析突变和正常皮肤成纤维细胞中的基因表达谱。目的II是研究VDR与Hairless（HR）的相互作用，HR是最近认识到的VDR的辅阻遏物。无毛基因的突变导致了一种与HVDRR中的脱发几乎相同的伴有丘疹性病变的脱发综合征（APL）。研究包括VDR和HR相互作用的检查，重点是HVDRR突变体。子目的包括：（a）研究HR作为VDR抑制剂和VDR功能调节剂的作用，（B）研究HR各种亚型的作用，（c）研究HVDRR中VDR和HR的相互作用，（d）研究APL突变体，（e）研究HR导致VDR稳定的机制，（f）研究HR的调节，（g）研究HR结合蛋白。我们的实验室团队在这些研究中拥有丰富的技能，多个合作者将增加他们的专业知识。该补助金是一项实质性的工作，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作用和激素抵抗。其意义将是开发和使用在VDR和HR中具有天然突变的细胞作为理想的试剂，其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耐药性，我们希望制定克服耐药性的策略，并为HVDRR或APL儿童开发更好的治疗方法，并找到增强骨化三醇作用的方法，以潜在地治疗骨质疏松症，癌症和牛皮癣等疾病。

DESCRIPTION (provided by applicant): 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 the VDR1 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.