权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of FGF23 in Chronic Kidney Disease (CKD) by iron and inflammation

铁和炎症对慢性肾脏病 (CKD) 中 FGF23 的调节

基本信息

批准号：
10659194
负责人：
Nicolae Valentin David
金额：
$ 60.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659194
关键词：
Acute Address Blood Circulation Brucella abortus Cardiac Cardiovascular system Cell Line Cell Lineage Cell Separation Cells Cessation of life Chronic Chronic Kidney Failure Circulation Coupled Data Development Diet Dietary Iron Disease Progression Enzymes Erythroid Erythroid Cells Flow Cytometry GALNT3 gene Genetic Genetic Transcription Goals Health Heart Diseases Hormones Impairment Individual Inflammation Inflammatory Injections Innovative Therapy Interleukin-1 beta Iron Kidney Lead Liver Macrophage Measures Metabolism MicroRNAs Minerals Modeling Morphology Mus Osteoblasts Osteocytes Patients Peptides Post-Translational Protein Processing Post-Translational Regulation Production Productivity Regulation Resources Role Serum Source Stimulus Testing Therapeutic Transfection Universities Untranslated Regions Wild Type Mouse adverse outcome antagonist bone bone cell dentin matrix protein 1 design fibroblast growth factor 23 improved improved outcome inhibitor innovation inorganic phosphate iron deficiency mimetics mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics pharmacologic premature prevent response skeletal skills therapeutic evaluation therapeutic target

项目摘要

PROJECT SUMMARY Fibroblast growth factor (FGF) 23 is a phosphate regulating hormone normally produced by bone. In chronic kidney disease (CKD), accumulation of circulating bioactive intact FGF23 (iFGF23), due to increased Fgf23 transcription and decreased FGF23 de-activating cleavage, is independently associated with cardiovascular mortality. Novel therapeutic approaches to reduce FGF23 levels and prevent adverse outcomes in CKD are desperately needed but current therapies are suboptimal. Iron deficiency (ID) and inflammation are powerful stimuli of FGF23 transcription and cleavage. In healthy mice, FGF23 production is highly increased in response to ID and inflammation, but only mild increases in serum iFGF23 levels are observed due to concomitant increase in FGF23 cleavage. miR-122 increases FGF23 cleavage and is highly elevated in response to ID and inflammation. In CKD, we show that the expression of miR-122 is reduced despite ID and inflammation, FGF23 cleavage is impaired, and ID and inflammation therefore contribute to increased iFGF23 levels. We showed that partial correction of ID or inflammatory component in mice with CKD reduced FGF23 transcription, corrected FGF23 levels and prevented development of cardiac disease and premature death. However, bone-specific deletion of FGF23 was not sufficient to fully correct FGF23 levels in iron deficient or inflamed mice, suggesting that additional cell targets produce FGF23 in response to ID and inflammation. In fact, we show that erythroid cells and macrophages also contribute to FGF23 excess. In this innovative proposal, we will test the hypothesis that erythroid and macrophage cell lineage contribute to increased production of FGF23 in response to ID and inflammation, and that lower miR-122 result in impaired FGF23 cleavage in health and in CKD. In Aim1, we will determine if FGF23 is produced by bone and macrophages in response to inflammation and by bone and erythroid cells in response to iron deficiency. We will use inflammatory challenges and dietary iron restriction in mice with cell lineage specific deletion of FGF23. In Aim2, we will assess the role of miR-122 in response to ID and inflammation on FGF23 cleavage using genetic deletion of miR-122 and administration of miR-122 antagonists in mice. In Aim 3, we will test the therapeutic potential of targeting the osteocytes, pre- osteoblasts, erythroid and macrophages in CKD, by using complementary genetic and pharmacological approaches to lower FGF23 in the Col4a3KO mouse model of CKD. We will also use genetic deletion of miR- 122 and administration of a miR-122 mimetic in mice with CKD to demonstrate the therapeutic potential of miR- 122 to increase FGF23 cleavage in CKD and prevent elevations of iFGF23 levels. We will measure FGF23 levels, and assess amelioration of kidney, bone and cardiac 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 regulation, and support our ultimate goal of developing novel therapies to improve adverse outcomes in CKD.

项目总结成纤维细胞生长因子23是一种磷酸调节激素，通常由骨骼产生。在慢性病肾脏疾病(CKD)，循环中生物活性完整的FGF23(IFGF23)积聚，原因是FGF23增加转录和FGF23失活裂解减少与心血管独立相关死亡率。降低慢性肾脏病FGF23水平和预防不良结局的新治疗方法是迫切需要，但目前的治疗方法并不理想。缺铁(ID)和炎症是强有力的刺激FGF23转录和切割。在健康的小鼠中，FGF23的产生大大增加与ID和炎症有关，但由于伴随的增加，仅观察到血清iFGF23水平的轻微增加在FGF23切割中。MIR-122增加FGF23的切割，并在ID和发炎。在CKD中，我们发现尽管存在ID和炎症，miR-122的表达仍然减少，FGF23 卵裂受损，ID和炎症因此导致iFGF23水平升高。我们向大家展示了部分纠正慢性肾脏病小鼠ID或炎症成分降低FGF23转录，已更正 FGF23水平，并防止心脏病和过早死亡的发展。但是，骨骼特定 FGF23的缺失不足以完全纠正缺铁或发炎小鼠的FGF23水平，这表明这些额外的细胞靶点会产生FGF23，以应对ID和炎症。事实上，我们发现红系细胞和巨噬细胞也是FGF23过量的原因之一。在这个创新的提案中，我们将检验这一假设红系和巨噬细胞系有助于增加FGF23的产生炎症，而miR-122降低会导致健康和慢性肾脏病患者FGF23裂解受损。在Aim1中，我们将确定FGF23是否由骨和巨噬细胞在炎症反应中产生，并通过骨骼和红系细胞对缺铁的反应。我们将使用炎症性挑战和膳食铁限制细胞系特异性缺失FGF23的小鼠。在AIM2中，我们将评估miR-122在通过miR-122基因缺失和给药对FGF23切割上的ID和炎症反应的反应小鼠体内有MIR-122拮抗剂。在目标3中，我们将测试靶向骨细胞的治疗潜力， CKD中的成骨细胞、红系和巨噬细胞在遗传和药理学上的互补作用降低CKD Col4a3KO小鼠模型中FGF23的途径我们还将使用miR-的基因缺失 122，并在CKD小鼠体内应用miR-122模拟物，以证明miR-122的治疗潜力。 122以增加CKD中FGF23的切割，并防止iFGF23水平的升高。我们将测量FGF23 水平，并评估肾脏、骨骼和心脏形态和功能的改善情况。这些创新的目标由西北大学拥有专业知识、技能和资源的高效协作团队提供支持这将进一步加深我们对FGF23规则的理解，并支持我们开发改善慢性肾脏病不良结局的新疗法。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptomics: a Solution for Renal Osteodystrophy?

DOI：
10.1007/s11914-020-00583-6
发表时间：
2020-06
期刊：
Current osteoporosis reports
影响因子：
4.3
作者：
Martin A;David V
通讯作者：
David V

FGF-23 and sclerostin in serum and bone of CKD patients.

DOI：
10.5414/cn111111
发表时间：
2023-05
期刊：
Clinical nephrology
影响因子：
1.1
作者：
Lima F;Monier-Faugere MC;Mawad H;David V;Malluche HH
通讯作者：
Malluche HH

Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.

DOI：
10.1097/mnh.0000000000000614
发表时间：
2020-07
期刊：
Current opinion in nephrology and hypertension
影响因子：
3.2
作者：
Courbon G;Martinez-Calle M;David V
通讯作者：
David V

Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy.

DOI：
10.1172/jci159928
发表时间：
2023-06-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Martinez-Calle, Marta;Courbon, Guillaume;Hunt-Tobey, Bridget;Francis, Connor;Spindler, Jadeah;Wang, Xueyan;Reis, Luciene M. dos;Martins, Carolina S. W.;Salusky, Isidro B.;Malluche, Hartmut;Nickolas, Thomas L.;Moyses, Rosa M. A.;David, Valentin;Martin, Aline
通讯作者：
Martin, Aline

Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease.

DOI：
10.1038/s41413-021-00154-0
发表时间：
2021-08-02
期刊：
Bone research
影响因子：
12.7
作者：
Courbon G;Francis C;Gerber C;Neuburg S;Wang X;Lynch E;Isakova T;Babitt JL;Wolf M;Martin A;David V
通讯作者：
David V