VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

维生素 D 受体和激素反应的调节

• 批准号: 7988347
• 负责人: David Feldman
• 金额: $ 4.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-11-30 至 2010-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988347
• 关键词: Abbreviations; Alopecia; Amino Acids; Animals; Apoptosis; Applications Grants; Area; Autoimmune Diseases; Binding Proteins; Biological Process; Biology; Brain; Bypass; Calcitriol; Caring; Case Study; Cell Proliferation; Cells; Cerebellum; Child; Clinical; Clinical Treatment; Clinical Trials; Data; Defect; Deformity; Dermatologist; Development; Diagnosis; Disease; Epidermis; Equilibrium; Familial hypophosphatemic bone disease; Fibroblasts; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Goals; Grant; Hair; Hair follicle structure; Hormonal; Hormones; Human; Human Biology; Inherited; International; Investigation; Knowledge; Laboratories; Lead; Lesion; Ligands; Light; Male Pattern Baldness; Malignant Neoplasms; Mediating; Methods; Molecular; Mutation; Nature; Nerve Degeneration; Organ; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenocopy; Physicians; Physiology; Play; Process; Progress Reports; Protein Isoforms; Proteins; Psoriasis; Reagent; Receptor Gene; Recovery of Function; Regulation; Research; Research Personnel; Resistance; Resistance development; Resources; Rickets; Role; Signal Pathway; Skin; Skin Abnormalities; Structure; Syndrome; Therapeutic; Tissues; Transactivation; Translating; Uncertainty; VDR interacting protein complex DRIP; Vitamin D; Vitamin D3 Receptor; Vitamins; analog; base; clinical application; experience; granule cell; help-seeking behavior; hormone regulation; hormone resistance; improved; information gathering; insight; mutant; novel; receptor; receptor function; research clinical testing; research study; resistance mechanism; response; skills; skin lesion; success; Abbreviations; Alopecia; Amino Acids; Animals; Apoptosis; Applications Grants; Area; Autoimmune Diseases; Binding Proteins; Biological Process; Biology; Brain; Bypass; Calcitriol; Caring; Case Study; Cell Proliferation; Cells; Cerebellum; Child; Clinical; Clinical Treatment; Clinical Trials; Data; Defect; Deformity; Dermatologist; Development; Diagnosis; Disease; Epidermis; Equilibrium; Familial hypophosphatemic bone disease; Fibroblasts; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Goals; Grant; Hair; Hair follicle structure; Hormonal; Hormones; Human; Human Biology; Inherited; International; Investigation; Knowledge; Laboratories; Lead; Lesion; Ligands; Light; Male Pattern Baldness; Malignant Neoplasms; Mediating; Methods; Molecular; Mutation; Nature; Nerve Degeneration; Organ; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenocopy; Physicians; Physiology; Play; Process; Progress Reports; Protein Isoforms; Proteins; Psoriasis; Reagent; Receptor Gene; Recovery of Function; Regulation; Research; Research Personnel; Resistance; Resistance development; Resources; Rickets; Role; Signal Pathway; Skin; Skin Abnormalities; Structure; Syndrome; Therapeutic; Tissues; Transactivation; Translating; Uncertainty; VDR interacting protein complex DRIP; Vitamin D; Vitamin D3 Receptor; Vitamins; analog; base; clinical application; experience; granule cell; help-seeking behavior; hormone regulation; hormone resistance; improved; information gathering; insight; mutant; novel; receptor; receptor function; research clinical testing; research study; resistance mechanism; response; skills; skin lesion; success

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.

这种修订的竞争性更新继续我们研究维生素D受体（VDR）在 调节对活性激素的反应，1,25-二羟基维生素D3（钙三醇）。我们的双重主题 研究是研究VDR在骨化三醇作用中的作用，并阐明具有抵抗力的机制 钙三醇。我们的目标是将VDR动作的知识转化为临床应用并改善钙化 治疗作为一种抗增殖和促分化的激素，用于治疗骨质疏松症， 瑞克，癌症等。赠款有两个具体的目标 VDR抗性。初步数据表明两个目标都是可行的。目的我继续研究 遗传性维生素D抗rick（HVDRR）的儿童由于Thevdr1突变而引起的疾病 引起对钙三醇作用的极端抗性。 Sub-aims将：（a）分析HVDRR的新案例，（b） 开发绕过电阻并挽救VDR缺陷的方法，（c）分析基因表达 突变体和正常皮肤成纤维细胞的剖面。 AIM II是对VDR与无毛的相互作用的研究 （HR），最近公认的VDR的共抑制剂。无毛基因的突变引起综合征 与HVDRR中的脱发相同的毛状病变（APL）的脱发。研究包括 对VDR和HR相互作用的检查，重点是HVDRR突变体。子iams包括（a）研究 HR作为VDR功能的VDR抑制器和调节剂的作用，（b）HR的各种同工型的作用，（C） HVDRR中的VDR和HR相互作用，以及（d）APL突变体中的（e）HR导致VDR的机制 稳定，（f）HR的调节和（g）搜索HR结合蛋白。我们的实验室小组具有丰富的技能 在这些研究中，多个合作者将增加其专业知识。赠款是一项艰巨的任务 检查VDR功能的许多方面，旨在理解钙化/VDR动作和 激素抗性。意义将是开发和利用VDR中具有天然突变的细胞 HR作为理想的试剂，允许逐步逐步进行钙化的作用机理。经过 阐明细胞如何抵抗钙化三醇的作用，我们希望制定克服策略 HVDRR或APL儿童的抵抗力和改进的治疗方法以及寻找方法 增强骨化三醇作用，以治疗诸如骨质疏松症，癌症和牛皮癣等疾病。