Molecular regulation of renal 125(OH)2D production

肾脏 125(OH)2D 产生的分子调节

• 批准号: 7142728
• 负责人: FARZANA PERWAD
• 金额: $ 12.18万
• 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/7142728
• 关键词: 1,25 dihydroxycholecalciferol; DNA footprinting; biological signal transduction; cytochrome P450; fibroblast growth factor; gel mobility shift assay; gene expression; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; mitogen activated protein kinase; nuclear runoff assay; phosphatidylinositol 3 kinase; phosphorylation; protein kinase C; renal tubule; tissue /cell culture; vitamin D; vitamin biosynthesis; vitamin metabolism; western blottings

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)2 D) 是钙 (Ca) 和磷 (Pi) 代谢的关键决定因素，对于骨骼生长和矿化至关重要。肾线粒体 1-α 羟化酶 (P450c1a) 是维生素 D -1,25(OH)2D 活性形式合成的限速步骤，该激素被肾脏和其他组织中的 24-羟化酶 (P450c24) 灭活。血清 1,25 OH)2D 浓度主要通过 PTH、Ca、Pi 和 1,25(OH)2 D 调节负责其合成和降解的酶来调节。维生素 D 代谢紊乱会因骨矿化异常而导致儿童佝偻病和成人骨软化症。成纤维细胞生长因子-23 (FGF-23) 是一种循环肽，最近在一组低磷血症综合征中发现，例如 X 连锁低磷血症性佝偻病 (XLH)，其特征是严重的肾磷酸盐消耗、血清 1,25(OH)2D 浓度过低和骨骼脱矿。 FGF-23 已被证明可通过抑制肾脏 1,25(OH)2D 的产生来降低血清 1,25(OH)2D 浓度。越来越多的证据表明，FGF-23 是 Pi、维生素 D 和骨代谢的重要生理调节剂，不依赖于 PTH，并且可能在慢性肾病中骨和矿物质稳态异常中发挥作用。关于 FGF-23 的作用及其调节维生素 D 代谢的机制还有很多东西有待了解。我们假设 FGF-23 直接作用于肾脏，调节 P450c1a 和 P450c24 基因表达，从而调节肾脏 1,25(OH)2 D 的产生。为了检验这一假设，我们提出以下目标 1 和 2：确定 FGF-23 在人和小鼠肾近曲小管细胞培养物中调节 P450c1a 和 P450c24 基因表达的转录和转录后机制。目标 3：表征 FGF-23 在体外和野生型、Hyp（XLH 小鼠模型）和 fgf-23 转基因小鼠体内调节肾小管细胞维生素 D 代谢的信号传导机制。 该研究计划旨在增进我们目前对肾脏中维生素 D 生成的了解，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 的产生将为治疗佝偻病儿童和肾衰竭患者的骨病提供新的治疗策略。