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Role of FGF23 and Phosphate in Chronic Kidney Disease

FGF23 和磷酸盐在慢性肾脏病中的作用

基本信息

批准号：
10544028
负责人：
Aline C Martin
金额：
$ 64.22万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544028
关键词：
ARNTL gene Acceleration Acute Adverse effects Affect American Animals Blood Pressure Cardiovascular system Cells Cessation of life ChIP-seq Chronic Chronic Kidney Failure Circadian Dysregulation Circadian Rhythms Clinical Data Development Diet Disease Disease Progression Enterobacteria phage P1 Cre recombinase Epidemic Equilibrium Event Familial hypophosphatemic bone disease Feedback Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptors Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Growth Homeostasis Human Impairment Individual Inflammation Inflammatory Kidney Kidney Diseases Knock-in Knowledge Link Longevity Luciferases Mediating Metabolism Minerals Modeling Molecular Molecular Target Morbidity - disease rate Morphology Mus Nuclear Outcome Pathology Pathway interactions Patients Periodicity Process Productivity Proteins Public Health Regimen Regulation Renal function Reporter Resources Role Serum Signal Transduction Slice Supplementation Testing Therapeutic Transcriptional Regulation Universities Wild Type Mouse adverse outcome arm bone circadian circadian pacemaker dietary fibroblast growth factor 23 genetic approach improved in vivo inhibitor innovation inorganic phosphate kidney cell molecular clock mortality mouse model novel novel therapeutic intervention novel therapeutics overexpression pharmacologic prevent response skills therapeutic target transcriptome sequencing

项目摘要

PROJECT SUMMARY In chronic kidney disease (CKD), hyperphosphatemia and increased fibroblast growth factor 23 (FGF23) levels are associated with faster CKD progression, cardiovascular events and death. Novel therapeutic approaches to limit the effects of excess FGF23 and phosphate (Pi), slow CKD progression and prevent adverse outcomes are desperately needed. In preliminary data for this project, chronic administration of FGF23 or dietary Pi supplementation that further increased FGF23 levels in mice with CKD, accelerate CKD progression. In addition, we show that FGF23 and Pi are powerful regulators of circadian rhythms in the kidney. Impaired circadian rhythms, or chronodisruption, is an established feature of CKD, but the factors contributing to altered expression of kidney clock genes, and the consequences on kidney function and mortality remain unclear. FGF23 and Pi activate FGF receptor 1 (FGFR1), increase early growth response protein 1 (EGR1) activation and stimulate nuclear factor κB (NFκB), an established inhibitor of the repressor arm of the core molecular clock. We show that administration of an FGFR1 inhibitor in FGF23-treated kidney cells and in mice with CKD reduces EGR1 expression and corrects the expression of clock genes in the kidney. Importantly, we show that FGFR1 inhibitor improved kidney function in mice with CKD. In this innovative proposal, we will test the hypothesis that increased FGF23 and Pi accelerate CKD progression through disruption of the kidney circadian clock, and that this process is mediated by FGFR1. In Aim 1, we will define the combined and individual roles of FGF23 and Pi on kidney function and identify their kidney-specific molecular targets. We will use low and high dietary Pi administration, FGF23 administration and bone-specific Fgf23 deletion in the wild-type (WT) and Col4a3KO mouse model of progressive CKD. In Aim 2, we will assess the role of EGR1 and NFκB in mediating the effects of FGF23 and Pi on the kidney molecular clock. We will use genetic and pharmacological approaches to modulate EGR1 and NFκB signaling, and assess transcriptional oscillations of kidney clock genes in models of acute and chronic FGF23 and Pi excess. We will identify kidney-specific gene targets using EGR1 and NFκB ChIP sequencing. In Aim 3, we will demonstrate the contribution of increased Bmal1, one of the main core clock activators, to impaired kidney function using genetic approaches to lower kidney Bmal1 expression in WT and Co4a3KO mice. We will also use genetic and pharmacologic blockade of FGFR1 in mice with CKD to demonstrate its therapeutic potential to prevent FGF23 and Pi induced inflammation on the kidney and restore kidney circadian rhythms. We will assess amelioration of lifespan, markers of mineral metabolism and kidney morphology and function. These innovative aims are supported by a productive collaborative team with expertise, skills and resources at Northwestern University that will further develop our understanding of FGF23 and Pi function, and support our ultimate goal of developing novel therapies to improve CKD-associated outcomes.

项目概要慢性肾病 (CKD)、高磷血症和成纤维细胞生长因子 23 (FGF23) 水平升高与更快的 CKD 进展、心血管事件和死亡相关。新的治疗方法限制过量 FGF23 和磷酸盐 (Pi) 的影响、减缓 CKD 进展并预防不良后果迫切需要。在该项目的初步数据中，长期施用 FGF23 或膳食 Pi 补充进一步增加 CKD 小鼠 FGF23 水平，加速 CKD 进展。此外，我们证明 FGF23 和 Pi 是肾脏昼夜节律的强大调节剂。昼夜节律受损节律或时间紊乱是 CKD 的一个既定特征，但导致表达改变的因素肾钟基因的变化，以及对肾功能和死亡率的影响仍不清楚。 FGF23 和 Pi 激活 FGF 受体 1 (FGFR1)，增加早期生长反应蛋白 1 (EGR1) 激活并刺激核因子 κB (NFκB)，一种已确定的核心分子钟阻遏臂抑制剂。我们展示在 FGF23 处理的肾细胞和患有 CKD 的小鼠中施用 FGFR1 抑制剂可减少 EGR1 表达并纠正肾脏中时钟基因的表达。重要的是，我们证明 FGFR1 抑制剂改善患有 CKD 的小鼠的肾功能。在这个创新提案中，我们将测试增加的假设 FGF23 和 Pi 通过扰乱肾脏生物钟来加速 CKD 进展，并且该过程由 FGFR1 介导。在目标 1 中，我们将定义 FGF23 和 Pi 对肾功能的联合和单独作用，并确定它们的作用肾脏特异性分子靶点。我们将使用低和高膳食 Pi 给药、FGF23 给药和进行性 CKD 野生型 (WT) 和 Col4a3KO 小鼠模型中骨特异性 Fgf23 缺失。在目标 2 中，我们将评估 EGR1 和 NFκB 在介导 FGF23 和 Pi 对肾脏分子的影响中的作用钟。我们将使用遗传和药理学方法来调节 EGR1 和 NFκB 信号传导，并评估急性和慢性 FGF23 和 Pi 过量模型中肾钟基因的转录振荡。我们将使用 EGR1 和 NFκB ChIP 测序识别肾脏特异性基因靶标。在目标 3 中，我们将展示 Bmal1（主要核心时钟激活剂之一）增加对肾功能受损的贡献降低 WT 和 Co4a3KO 小鼠肾脏 Bmal1 表达的遗传方法。我们还将利用遗传和在 CKD 小鼠中对 FGFR1 进行药物阻断，以证明其预防 FGF23 的治疗潜力 Pi 会引起肾脏炎症并恢复肾脏昼夜节律。我们将评估改善情况寿命、矿物质代谢标志物以及肾脏形态和功能。这些创新目标是由西北大学富有成效的协作团队提供支持，该团队拥有专业知识、技能和资源，将进一步加深我们对 FGF23 和 Pi 功能的理解，并支持我们开发的最终目标改善 CKD 相关结果的新疗法。