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:
  • 金额:
    $ 63.8万
  • 依托单位:
  • 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

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 在慢性肾病(CKD)中,高磷血症和成纤维细胞生长因子23(FGF 23)水平升高 与CKD进展、心血管事件和死亡加快相关。新的治疗方法 限制过量FGF23和磷酸盐(Pi)的影响,减缓CKD进展并预防不良结局, 迫切需要的。在该项目的初步数据中,长期给予FGF23或膳食Pi 补充FGF23可进一步增加患有CKD的小鼠中的FGF23水平,加速CKD进展。此外,本发明还提供了一种方法, 我们表明FGF 23和Pi是肾脏中昼夜节律的强有力的调节剂。昼夜节律受损 节律或时间中断是CKD的既定特征,但导致表达改变的因素 肾时钟基因的表达,以及对肾功能和死亡率的影响尚不清楚。FGF23和Pi 激活FGF受体1(FGFR 1),增加早期生长反应蛋白1(EGFR 1)的激活,并刺激 核因子κB(NFκB),一种已确立的核心分子钟阻遏臂抑制剂。我们表明 在FGF23处理的肾细胞和患有CKD的小鼠中施用FGFR1抑制剂降低了EGFR 1 表达,并纠正肾脏中时钟基因的表达。重要的是,我们发现FGFR1抑制剂 改善CKD小鼠的肾功能。在这个创新的建议中,我们将测试增加的假设, FGF23和Pi通过破坏肾脏昼夜节律钟加速CKD进展, 由FGFR1介导。 在目标1中,我们将定义FGF 23和Pi对肾功能的联合和单独作用,并确定它们在肾功能中的作用。 肾脏特异性分子靶点。我们将使用低和高膳食Pi施用、FGF 23施用和低膳食Pi施用。 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EGFR 1和NFκB在介导FGF 23和Pi对肾脏分子的影响中的作用, 时钟我们将使用遗传学和药理学方法来调节EGFR 1和NFκB信号传导,并评估 急性和慢性FGF23和Pi过量模型中肾时钟基因的转录振荡。我们将 使用EGFR 1和NFκB ChIP测序鉴定肾脏特异性基因靶点。在目标3中,我们将展示 增加的Bmal 1(主要核心时钟激活剂之一)对肾功能受损的贡献, 通过遗传方法降低WT和Co4a3KO小鼠肾脏Bmal1表达。我们还将使用基因和 CKD小鼠中FGFR 1的药理学阻断,以证明其预防FGF23的治疗潜力 和Pi诱导的肾脏炎症和恢复肾脏昼夜节律。我们将评估改善情况 矿物质代谢和肾脏形态和功能的标志物。这些创新目标是 由西北大学富有成效的合作团队提供专业知识,技能和资源, 这将进一步发展我们对FGF23和Pi功能的理解,并支持我们的最终目标, 改善CKD相关结局的新疗法。

项目成果

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Aline C Martin其他文献

Aline C Martin的其他文献

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{{ truncateString('Aline C Martin', 18)}}的其他基金

Role of FGF23 and Phosphate in Chronic Kidney Disease
FGF23 和磷酸盐在慢性肾脏病中的作用
  • 批准号:
    10544028
  • 财政年份:
    2022
  • 资助金额:
    $ 63.8万
  • 项目类别:
The role of DMP1 in FGF23-induced hypophosphatemia
DMP1 在 FGF23 诱导的低磷血症中的作用
  • 批准号:
    10596626
  • 财政年份:
    2022
  • 资助金额:
    $ 63.8万
  • 项目类别:
Professional Development Core
专业发展核心
  • 批准号:
    10657777
  • 财政年份:
    2021
  • 资助金额:
    $ 63.8万
  • 项目类别:
Professional Development Core
专业发展核心
  • 批准号:
    10285157
  • 财政年份:
    2021
  • 资助金额:
    $ 63.8万
  • 项目类别:
Regulation of FGF23 by DMP1 in Health and in Chronic Kidney Disease (CKD)
DMP1 在健康和慢性肾脏病 (CKD) 中对 FGF23 的调节
  • 批准号:
    9314544
  • 财政年份:
    2015
  • 资助金额:
    $ 63.8万
  • 项目类别:
Regulation of FGF23 by DMP1 in Health and in Chronic Kidney Disease (CKD)
DMP1 在健康和慢性肾脏病 (CKD) 中对 FGF23 的调节
  • 批准号:
    8964715
  • 财政年份:
    2015
  • 资助金额:
    $ 63.8万
  • 项目类别:
Regulation of FGF23 by DMP1 in Health and in Chronic Kidney Disease (CKD)
DMP1 在健康和慢性肾脏病 (CKD) 中对 FGF23 的调节
  • 批准号:
    9750663
  • 财政年份:
    2015
  • 资助金额:
    $ 63.8万
  • 项目类别:
Regulation of FGF23 by DMP1 in Health and in Chronic Kidney Disease (CKD)
DMP1 在健康和慢性肾脏病 (CKD) 中对 FGF23 的调节
  • 批准号:
    9096079
  • 财政年份:
    2015
  • 资助金额:
    $ 63.8万
  • 项目类别:

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