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：
10344343
负责人：
Aline C Martin
金额：
$ 63.8万
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/10344343
关键词：
ARNTL gene 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 Pharmacology Process Proteins Public Health Regimen Regulation Renal function Reporter Resources Role Serum Signal Transduction Slice Supplementation Testing Therapeutic Universities Wild Type Mouse adverse outcome arm base 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 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.

项目摘要在慢性肾脏疾病（CKD）中，高磷酸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，心血管事件和死亡有关。新颖的治疗方法限制过量FGF23和磷酸盐（PI）的影响，CKD进展缓慢并防止不良后果迫切需要。在该项目的初步数据中，长期给予FGF23或饮食PI 补充CKD的小鼠进一步增加了FGF23水平，加速了CKD进展。此外，我们表明，FGF23和PI是肾脏中昼夜节律的强大调节因子。昼夜节律受损节奏或计时率是CKD的确定特征，但导致表达改变的因素肾时钟基因以及对肾功能和死亡率的后果尚不清楚。 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），核心分子时钟的复制臂的抑制剂。我们显示在FGF23处理的肾细胞和CKD小鼠中施用FGFR1抑制剂可降低EGR1 表达并纠正肾脏中时钟基因的表达。重要的是，我们表明FGFR1抑制剂 CKD小鼠的肾功能改善。在这项创新的提议中，我们将检验以下假设，即增加 FGF23和PI通过破坏肾脏昼夜节律加速了CKD的进展，并且此过程由FGFR1介导。在AIM 1中，我们将定义FGF23和PI在肾脏功能上的合并和个体作用，并确定其肾脏特异性分子靶标。我们将使用低饮食和高饮食PI给药，FGF23给药和野生型（WT）和COL4A3KO小鼠模型的骨特异性FGF23缺失。在AIM 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物方法来调节EGR1和NFκB信号，并评估急性FGF23和PI模型中肾时钟基因的转录振荡超过了。我们将使用EGR1和NFκB芯片测序确定肾脏特异性基因靶标。在AIM 3中，我们将证明 BMAL1（主要核心时钟激活剂之一）增加的肾脏功能的贡献 WT和CO4A3KO小鼠中较低肾脏BMAL1表达的遗传方法。我们还将使用遗传和 CKD小鼠中FGFR1的药理阻滞，以证明其预防FGF23的治疗潜力 PI引起肾脏和恢复肾脏昼夜节律的炎症。我们将评估改善寿命，矿物质代谢和肾脏形态和功能的标记。这些创新的目标是在西北大学拥有专业知识，技能和资源的富有成效的合作团队的支持下将进一步发展我们对FGF23和PI功能的理解，并支持我们开发的最终目标改善CKD相关结果的新型疗法。