VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

描述（由申请人提供）：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）反应中的作用的研究。我们研究的双重主题是研究VDR在骨化三醇作用中的作用和阐明对骨化三醇的抗性机制。我们的目标是将VDR作用的知识转化为临床应用，并改进骨化三醇作为抗增殖和促分化激素的治疗方法，用于治疗骨质疏松症、佝偻病、癌症等。该基金有两个具体目标，都与骨化三醇的作用和VDR耐药机制有关。初步数据表明，这两个目标都是可行的。Aim I继续我们对遗传性维生素D抗性佝偻病（HVDRR）儿童的研究，这种疾病是由于VDR1突变导致对骨化三醇的作用产生极端抗性。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)分析突变和正常皮肤成纤维细胞中的基因表达谱。Aim II是一项研究VDR与hahairless （HR）的相互作用，这是最近发现的VDR的共同抑制因子。无毛基因突变导致斑秃伴丘疹病变（APL）综合征，与HVDRR中的斑秃几乎相同。研究包括检查VDR和HR的相互作用，重点是HVDRR突变体。子目标包括(a)研究HR作为VDR抑制剂和VDR功能调节剂的作用，(b)各种HR同种异构体的作用，(c) VDR和HR在HVDRR中的相互作用，(d)在APL突变体中的作用，(e) HR导致VDR稳定的机制，(f) HR调节和(g)寻找HR结合蛋白。我们的实验室团队在这些研究中具有丰富的技能，并且多个合作者将增加他们的专业知识。这项拨款是一项实质性的工作，研究了VDR功能的许多方面，所有这些都是为了了解骨化三醇/VDR的作用和激素耐药性。其意义在于开发和利用VDR和HR自然突变的细胞作为理想试剂，使骨化三醇的作用机制逐步相互作用。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，并为患有HVDRR或APL的儿童开发改进的治疗方法，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.