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: 7669168
• 负责人: FARZANA PERWAD
• 金额: $ 12.58万
• 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/7669168
• 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 Culture Techniques; Cell Line; Cells; Child; Chronic Kidney Failure; DNA-Protein Interaction; Data; Defect; Dihydroxycholecalciferols; Disease; Electrophoretic Mobility Shift Assay; Elements; 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; 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; Pathway interactions; Patients; Peptides; Phosphorus; Phosphorylation; Phosphotransferases; Physiologic calcification; Physiological; Play; Production; Protein Kinase C; Proximal Kidney Tubules; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Reporter; Reporting; Research Personnel; Research Proposals; Ribonucleases; Rickets; Rodent; Role; Run-On Assays; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; 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; skeletal; 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)： 1，25-二羟基维生素D(1，25(OH)2D)是钙(Ca)和磷(PI)代谢的关键决定因素，对骨生长和矿化是必不可少的。肾脏线粒体1-α羟基酶(P450c1a)是合成维生素D-1，25(OH)2D活性形式的限速步骤，在肾脏和其他组织中，该激素被24-羟基酶(P450c24)失活。血清1，25(OH)2D浓度受PTH、Ca、PI和1，25(OH)2D的调节，主要是通过调节负责其合成和降解的酶来实现的。维生素D代谢紊乱会导致儿童软骨病和成人骨软化症，原因是骨骼矿化异常。成纤维细胞生长因子-23(成纤维细胞生长因子-23)是一种循环肽，最近在一组低磷血症综合征中被发现，如X-连锁低磷酸盐血症(XLH)，其特征是严重的肾脏磷酸盐消耗，不适当的血清1，25(OH)2D浓度和骨骼脱矿。已有研究表明，成纤维细胞生长因子-23通过抑制肾脏1，25(OH)2D的生成来降低血清1，25(OH)2D浓度。有证据表明，成纤维细胞生长因子-23是PI、维生素D和骨代谢的重要生理调节因子，不依赖甲状旁腺素，可能在慢性肾脏疾病的骨和矿物质平衡异常中发挥作用。关于成纤维细胞生长因子-23的作用以及它调节维生素D代谢的机制还有很多需要了解。我们推测，成纤维细胞生长因子-23直接作用于肾脏，调节P450c1a和P450c24基因的表达，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-目的1和2：确定成纤维细胞生长因子-23调节人和小鼠肾近端小管上皮细胞P450c1a和P450c24基因表达的转录和转录后机制。目的：研究成纤维细胞生长因子-23调控肾小管上皮细胞维生素D代谢的信号转导机制，包括肾小管上皮细胞、小鼠肾小管上皮细胞和体内转基因小鼠。 这项研究建议旨在提高我们目前对肾脏中维生素D产生的了解，并为维生素D合成异常的疾病状况提供新的见解。了解各种因素如何控制维生素D的产生，将为治疗软骨病儿童和肾衰竭患者的骨病提供新的治疗策略。