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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：
10434127
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/10434127
关键词：
Acute Address Blood Circulation Brucella abortus Cardiac Cardiac development Cardiovascular system Cell Line Cell Lineage Cells Cessation of life Chronic Chronic Kidney Failure Coupled Data Diet Dietary Iron Disease Progression Enzymes Erythroid Erythroid Cells FGF1 gene 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 Liver Circulation Measures Metabolism MicroRNAs Minerals Modeling Morphology Mus Osteoblasts Osteocytes Patients Peptides Pharmacology Post-Translational Protein Processing Post-Translational Regulation Production Regulation Resources Role Serum Source Stimulus Testing Therapeutic Transcriptional Regulation Universities Untranslated Regions Wild Type Mouse adverse outcome antagonist base bone bone cell dentin matrix protein 1 design fibroblast growth factor 23 improved improved outcome inhibitor innovation inorganic phosphate iron deficiency macrophage mimetics mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics 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