The Role of FGF23 in the Pathogenesis of Chronic Kidney Disease

FGF23 在慢性肾脏病发病机制中的作用

• 批准号: 8538953
• 负责人: ANSEL PHILIP AMARAL
• 金额: $ 4.17万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538953
• 关键词: 1,25 (OH) vitamin D; Accounting; Actins; Adult; Affect; Apoptosis; Area; Award; Biological Markers; Biology; Budgets; Calcitriol; Cardiovascular Diseases; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Cytoskeleton; Data; Defect; Development; Dialysis patients; Dialysis procedure; Disease; Disease Progression; Distal convoluted renal tubule structure; Doctor of Philosophy; Economics; Endocrine; Environment; Event; Excretory function; FGF2 gene; Filtration; Foot Process; Funding; Genetic; Goals; Health; Healthcare; Homeostasis; Hormones; Hypertrophy; In Vitro; Injury; International; Intervention; Kidney; Laboratories; Left; Life; Longevity; Mediating; Mediator of activation protein; Medicare; Mentorship; Metabolic; Minority; Modeling; Molecular; Morphology; Mus; Nature; Nephrons; Osteocytes; Parathyroid gland; Pathogenesis; Pathway interactions; Patients; Pattern; Phosphorus Metabolism Disorders; Physicians; Play; Population; Process; Production; Proteinuria; Public Health; Publications; Publishing; Quality of life; Regulation; Renal function; Research; Research Personnel; Risk; Role; Scientist; Series; Serum; Signal Pathway; Signal Transduction; Students; Surface; T-Cell Activation; Testing; Training Programs; Translational Research; United States National Institutes of Health; Universities; Vitamin D; Wolves; Work; base; cell growth; cell type; exhaust; fibroblast growth factor 23; in vivo; in vivo Model; innovation; inorganic phosphate; mortality; new therapeutic target; novel; nuclear factors of activated T-cells; podocyte; premature; programs; public health relevance; research study; response; urinary; 1,25 (OH) vitamin D; Accounting; Actins; Adult; Affect; Apoptosis; Area; Award; Biological Markers; Biology; Budgets; Calcitriol; Cardiovascular Diseases; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Cytoskeleton; Data; Defect; Development; Dialysis patients; Dialysis procedure; Disease; Disease Progression; Distal convoluted renal tubule structure; Doctor of Philosophy; Economics; Endocrine; Environment; Event; Excretory function; FGF2 gene; Filtration; Foot Process; Funding; Genetic; Goals; Health; Healthcare; Homeostasis; Hormones; Hypertrophy; In Vitro; Injury; International; Intervention; Kidney; Laboratories; Left; Life; Longevity; Mediating; Mediator of activation protein; Medicare; Mentorship; Metabolic; Minority; Modeling; Molecular; Morphology; Mus; Nature; Nephrons; Osteocytes; Parathyroid gland; Pathogenesis; Pathway interactions; Patients; Pattern; Phosphorus Metabolism Disorders; Physicians; Play; Population; Process; Production; Proteinuria; Public Health; Publications; Publishing; Quality of life; Regulation; Renal function; Research; Research Personnel; Risk; Role; Scientist; Series; Serum; Signal Pathway; Signal Transduction; Students; Surface; T-Cell Activation; Testing; Training Programs; Translational Research; United States National Institutes of Health; Universities; Vitamin D; Wolves; Work; base; cell growth; cell type; exhaust; fibroblast growth factor 23; in vivo; in vivo Model; innovation; inorganic phosphate; mortality; new therapeutic target; novel; nuclear factors of activated T-cells; podocyte; premature; programs; public health relevance; research study; response; urinary

DESCRIPTION (provided by applicant): This is an F30 application to study the effects of fibroblast growth factor 23 (FGF23) on podocytes by Ansel Amaral, an MD/PhD student at the University of Miami. The PI was a previous recipient of the NIH Physician Scientist Training Program award (1R25DK059644-01) and is already actively involved in the laboratory's translational research program, marked by one recently submitted first author publication. Sponsor and Environment: The primary sponsor, Peter Mundel, is an international expert in podocyte biology. He has been continuously funded by NIH since 2001 and has an extensive track record of laboratory mentorship. The Co-Sponsor, Myles Wolf, is an international expert in FGF23 research and also an NIH funded investigator with an extensive track record of mentorship. Christian Faul, another Co-Sponsor, is an expert in podocyte cell signaling. The PI has access to a rich environment for scientific development led by his Sponsors' complementary expertise in the areas of FGF23, podocyte biology, and clinical research. Proposal: Chronic kidney disease (CKD) is a growing worldwide public health concern. Over 11% of adults living in the US are estimated to suffer from CKD, which leads to a diminished quality of life, financial health burden and premature death. Disordered phosphorus metabolism is one of the most common complications that contribute to decreased lifespan in CKD. An early manifestation of disordered phosphorus metabolism in CKD is increased secretion of FGF23 by osteocytes. FGF23 is a recently discovered endocrine hormone that increases urinary phosphate excretion and inhibits renal calcitriol production. Through these effects, FGF23 helps maintain normal serum phosphate levels in CKD patients despite progressive reduction in the renal capacity to excrete phosphate. Recent data from the Co-Sponsor demonstrated that increased FGF23 levels in CKD patients are independently associated with progression of CKD, cardiovascular disease and death. Whether direct effects of FGF23 mediate these findings has not yet been studied in detail. The purpose of this proposal is to test the hypothesis that FGF23 exerts direct effects on renal podocytes, which have been implicated as the target cells of several patterns of renal injury in innovative work performed by the Sponsor's laboratory. Our preliminary data indicate that cultured podocytes respond to FGF23 by displaying changes in the dynamics of the actin cytoskeleton and undergoing hypertrophic cell growth. We plan to extend these in vitro experiments and propose novel in vivo models to further characterize the pathological effects of FGF23 on podocyte morphology and function. We hypothesize that FGF23 excess initially induces reversible changes such as podocyte foot process effacement and hypertrophy, followed by irreversible injury leading to podocyte loss and eventually to total nephron and overall kidney damage. Given that FGF23 levels rise beginning in early CKD, the results would highlight FGF23 and its downstream signaling pathways in podocytes as a novel target for clinical intervention aimed at reducing the burden of CKD and its associated complications. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) affects over 11% of the US population, is disproportionately elevated in minority populations and those of lower economic status, and accounts for nearly $60 billion in healthcare spending, nearly 30% of the annual Medicare budget. Substantial clinical evidence has indicated that serum fibroblast growth factor 23 (FGF23) levels rise early in the course of CKD and are independently associated with mortality in patients suffering from CKD; however, so far FGF23 has only been considered as a potential biomarker for CKD, rather than a molecular factor that can directly cause the disease. This research endeavors to determine the direct pathological effects of FGF23 on podocytes and on the glomerular filter function of the kidney, with the eventual aim of revealing a novel therapeutic target for CKD.

描述（由申请人提供）：这是研究成纤维细胞生长因子23（FGF23）对迈阿密大学MD/PHD学生Ansel Amaral的影响的F30应用。 PI是NIH医师科学家培训计划奖（1R25DK059644-01）的先前获得者，并且已经积极参与了实验室的转化研究计划，这是最近提交的第一作者出版物的标志。赞助商和环境：主要赞助商彼得·蒙德尔（Peter Mundel）是足细胞生物学的国际专家。自2001年以来，他一直由NIH持续资助，并拥有实验室指导的广泛记录。共同发起人迈尔斯·沃尔夫（Myles Wolf）是FGF23研究的国际专家，也是NIH资助的研究人员，具有广泛的指导记录。另一个共同赞助商克里斯蒂安·福尔（Christian Faul）是足细胞信号传导的专家。 PI可以通过其赞助商在FGF23，Podocyte生物学和临床研究领域的互补专业知识领导的科学发展环境中获得丰富的环境。提案：慢性肾脏疾病（CKD）是全球不断增长的公共卫生问题。据估计，居住在美国的成年人中有11％的成年人患有CKD，这导致生活质量，财务健康负担和过早死亡的质量下降。磷代谢无序是最常见的并发症之一，导致CKD寿命下降。 CKD中磷代谢无序代谢的早期表现是骨细胞对FGF23的分泌增加。 FGF23是一种最近发现的内分泌激素，可增加泌尿磷酸盐排泄并抑制肾钙化生产。通过这些作用，尽管肾脏排泄磷酸盐的肾脏能力逐渐降低，但FGF23有助于维持CKD患者的正常血清磷酸盐水平。共同提案者的最新数据表明，CKD患者的FGF23水平升高与CKD，心血管疾病和死亡的进展独立相关。 FGF23的直接影响是否介导这些发现尚未详细研究。该提案的目的是检验以下假设：FGF23对肾足细胞产生直接影响，这被认为是发起人实验室进行创新工作的几种肾脏损伤模式的目标细胞。我们的初步数据表明，培养的足细胞通过显示肌动蛋白细胞骨架的动力学和经历肥大细胞生长的变化来对FGF23做出反应。我们计划扩展这些体外实验，并提出新型体内模型，以进一步表征FGF23对足细胞形态和功能的病理影响。我们假设FGF23过量最初会引起可逆的变化，例如足小脚步的过程和肥大，随后是不可逆转的损伤，导致足细胞丧失，最终导致总肾脏和整体肾脏损害。鉴于FGF23水平从早期CKD开始上升，结果将突出显示FGF23及其下游信号通路，这是临床干预措施的新靶标，旨在减轻CKD的负担及其相关的并发症。 公共卫生相关性：慢性肾脏疾病（CKD）影响了美国人口的11％以上，少数群体人口和经济状况较低的人数不成比例地升高，占医疗保健支出的近600亿美元，占年度医疗保险预算的近30％。大量的临床证据表明，血清成纤维细胞生长因子23（FGF23）水平在CKD过程中升高，并且与患有CKD患者的死亡率独立相关。但是，到目前为止，FGF23仅被认为是CKD的潜在生物标志物，而不是可以直接引起该疾病的分子因素。这项研究努力确定FGF23对足细胞和肾脏肾小球滤波功能的直接病理影响，最终揭示了针对CKD的新型治疗靶标。