Molecular regulation of renal 125(OH)2D production by Fibroblast Growth Factor23

成纤维细胞生长因子 23 对肾脏 125(OH)2D 产生的分子调节

• 批准号: 7472293
• 负责人: FARZANA PERWAD
• 金额: $ 12.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472293
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; 3' Untranslated Regions; Address; Adult; Biochemical; Biological Assay; Bone Diseases; Bone Growth; Calcium; Cell Line; Cells; Child; Chronic Kidney Failure; Condition; Cultured Cells; DNA-Protein Interaction; Data; Defect; Dihydroxycholecalciferols; Disease; Disruption; Electrophoretic Mobility Shift Assay; Elements; Endoribonucleases; Enzymes; Familial hypophosphatemic bone disease; Fibroblasts; Gene Expression; Genes; Growth; Homeostasis; Hormones; Human; Hypophosphatemia; In Vitro; Inherited; Iodine; Kidney; Kidney Failure; Knowledge; Laboratory Study; Learning; Localized; Mediating; Messenger RNA; Metabolism; Minerals; Mitochondria; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Mixed Function Oxygenases; Modeling; Molecular; Mus; Nuclear; Nucleic Acid Regulatory Sequences; Osteomalacia; Pancreatic ribonuclease; Pathway interactions; Patients; Peptides; Phosphorus; Phosphorylation; Phosphotransferases; Physiologic calcification; Physiological; Play; Polymerase Chain Reaction; Production; Protein Kinase C; Proximal Kidney Tubules; RNA-Binding Proteins; RNA-Protein Interaction; Rate; Regulation; Reporter; Reporting; Research Personnel; Research Proposals; Ribonucleases; Rickets; Rodent; Role; Run-On Assays; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Skeletal system; Syndrome; System; Testing; Time; Tissue Differentiation; Tissues; Transcription Initiation; Transgenic Mice; Tubular formation; Vitamin D; Vitamins; Wild Type Mouse; bone; bone metabolism; demineralization; enzyme activity; extracellular; fibroblast growth factor 23; in vivo; inhibitor/antagonist; inorganic phosphate; insight; interest; mRNA Stability; mineralization; novel; novel therapeutics; programs; promoter; research study; small molecule; wasting

DESCRIPTION (provided by applicant): 1,25-dihydroxyvitamin D (1,25(OH)2 D) is a critical determinant of calcium (Ca) and phosphorus (Pi) metabolism and is essential for bone growth and mineralization. Renal mitochondrial 1-alpha hydroxylase (P450c1a) enzyme is the rate limiting step in the synthesis of the active form of vitamin D -1,25(OH)2D, and the hormone is inactivated by the enzyme 24-hydroxylase (P450c24) in the kidney and other tissues. Serum 1,25 OH)2D concentration is regulated by PTH, Ca, Pi and 1,25(OH)2 D primarily by regulation of the enzymes responsible for its synthesis and degradation. Disorders of vitamin D metabolism causes rickets in children and osteomalacia in adults due to abnormal bone mineralization. Fibroblast Growth Factor-23 (FGF- 23) is a circulating peptide, recently identified in a group of hypophosphatemic syndromes such as X-linked hypophosphatemic rickets (XLH) that is characterized by severe renal phosphate wasting, inappropriately low serum 1,25(OH)2D concentrations, and skeletal demineralization. FGF-23 has been shown to decrease serum 1,25(OH)2D concentrations by suppressing renal 1,25(OH)2D production. Evidence is emerging that FGF-23 is an important physiologic regulator of Pi, vitamin D, and bone metabolism, independent of PTH, and may play a role in abnormal bone and mineral homeostasis in chronic kidney disease. Much remains to be learnt about the actions of FGF-23 and the mechanisms by which it regulates vitamin D metabolism. We hypothesize that FGF-23 acts directly on the kidney to regulate P450c1a and P450c24 gene expression and thereby regulates renal 1,25(OH)2 D production. To test this hypothesis, we propose the following -Aims1&2: Determine the transcriptional and post-transcriptional mechanisms by which FGF-23 regulates P450c1a and P450c24 gene expression in human and mouse renal proximal tubule cell cultures. Aim 3: Characterize the signaling mechanisms by which FGF-23 regulates vitamin D metabolism in renal tubular cells in vitro and in wild type, Hyp (a murine model of XLH), and fgf-23 transgenic mice in vivo. This research proposal is aimed at advancing our current knowledge about vitamin D production in the kidney and provide novel insights in disease conditions where vitamin D synthesis is abnormal. Understanding how various factors control vitamin D production will provide new therapeutic strategies to treat bone disease in children with rickets, and in patients suffering from kidney failure.

描述（由申请人提供）： 1，25-二羟维生素D（1，25（OH）2 D）是钙（Ca）和磷（Pi）代谢的关键决定因素，对骨生长和矿化至关重要。肾脏线粒体1-α羟化酶（P450 c1 a）是合成活性形式维生素D-1，25（OH）2D的限速步骤，并且该激素在肾脏和其他组织中被酶24-羟化酶（P450 c24）灭活。血清1，25（OH）2D浓度受PTH、Ca、Pi和1，25（OH）2D调节，主要通过调节负责其合成和降解的酶。维生素D代谢紊乱导致儿童佝偻病和成人骨软化症，这是由于骨矿化异常。成纤维细胞生长因子-23（FGF- 23）是一种循环肽，最近在一组低磷酸盐血症综合征中发现，如X连锁低磷酸盐血症佝偻病（XLH），其特征是严重的肾磷酸盐消耗，不适当的低血清1，25（OH）2D浓度和骨骼脱矿。已显示FGF-23通过抑制肾1，25（OH）2D产生来降低血清1，25（OH）2D浓度。有证据表明，FGF-23是Pi、维生素D和骨代谢的重要生理调节剂，独立于PTH，并且可能在慢性肾脏疾病的异常骨和矿物质稳态中起作用。关于FGF-23的作用及其调节维生素D代谢的机制仍有许多有待了解。我们推测FGF-23直接作用于肾脏，调节P450 c1 a和P450 c24基因表达，从而调节肾脏1，25（OH）2D的产生。为了验证这一假设，我们提出了以下目标1&2：确定FGF-23调节人和小鼠肾近端小管细胞培养物中P450 c1 a和P450 c24基因表达的转录和转录后机制。目标3：表征FGF-23调节体外肾小管细胞和体内野生型、Hyp（XLH小鼠模型）和fgf-23转基因小鼠中维生素D代谢的信号传导机制。 这项研究提案旨在推进我们目前对肾脏中维生素D产生的认识，并为维生素D合成异常的疾病提供新的见解。了解各种因素如何控制维生素D的产生将为佝偻病儿童和肾衰竭患者的骨骼疾病提供新的治疗策略。