Regulation of Fibroblast Growth Factor 23 by Iron and Anemia in Chronic Kidney Disease

慢性肾病中铁和贫血对成纤维细胞生长因子 23 的调节

• 批准号: 9224596
• 负责人: Mark Robert Hanudel
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224596
• 关键词: Address; Adult; Affect; American; Anemia; Bone Diseases; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Chelating Agents; Child; Childhood; Chronic Kidney Failure; Clinical Research; Clinical Sciences; Complex; Development; Development Plans; Disease Progression; Dose; Enzymes; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Ethics; Etiology; Glomerular Filtration Rate; Grant; Hormones; Human; Hypoxia Inducible Factor; Institutes; Institution; Iron; Iron deficiency anemia; Kidney; Knockout Mice; Knowledge; Lead; Left; Length; Manuscripts; Master of Science; Mediating; Mentors; Metabolism; Minerals; Mixed Function Oxygenases; Molecular Biology; Morbidity - disease rate; Mus; Normal Range; Osteocytes; PTH gene; Patients; Physicians; Physiological; Play; Population; Preparation; Procollagen-Proline Dioxygenase; Production; Public Health; Regimen; Regulation; Renal function; Research; Research Personnel; Resources; Risk Factors; Role; Scientist; Signal Pathway; Staging; Therapeutic; Training; Translational Research; Universities; Ventricular; Vitamin D2; Work; Writing; analog; bone; career; career development; design; fibroblast growth factor 23; hepcidin; improved; in vitro Model; inhibitor/antagonist; innovation; inorganic phosphate; insight; iron deficiency; iron metabolism; mortality; mouse model; novel; pediatric patients; prevent; programs; recombinant human erythropoietin; ventricular hypertrophy

PROJECT SUMMARY / ABSTRACT This proposal outlines a 4-year career development plan for Dr. Mark Hanudel, a pediatric nephrologist beginning an academic career as a physician-scientist. The program is designed to help him develop into an independent and productive scientific researcher at the forefront of the field of FGF23 metabolism, and eventually in other aspects of chronic kidney disease-mineral bone disorder (CKD-MBD). FGF23 is a bone- derived phosphaturic hormone, levels of which increase very early in CKD and are associated with adverse “off target” effects, including increased overall mortality, increased cardiovascular morbidity, and the development of ventricular hypertrophy. Physiologic regulation of FGF23 is complex, multifaceted, and remains incompletely understood. In addition to mineral metabolism factors, iron deficiency and erythropoietin have been shown to affect FGF23 production and metabolism. As iron deficiency anemia and erythropoietin use are exceedingly common in the CKD population, these novel determinants of FGF23 are especially relevant and deserving of further study. Insights into how iron and erythropoietin affect FGF23 may lead to new CKD therapeutic strategies aimed at reducing CKD-associated cardiovascular morbidity and mortality. Dr. Hanudel will benefit from close interactions with his primary mentors, Dr. Tomas Ganz, a leader in the fields of anemia and iron metabolism, and Dr. Isidro Salusky, a leader in the fields of mineral metabolism and CKD. Through UCLA’s Clinical and Translational Science Institute (CTSI) and Children’s Discovery and Innovation Institute (CDI), Dr. Hanudel will have access to numerous career development seminars addressing such topics as grant writing, manuscript preparation, and ethical research. He will take graduate courses to obtain further training in molecular biology, and will also complete and defend his Master of Science in Clinical Research thesis, furthering his biostatistical training. Dr. Hanudel has the full support of his institution, and his career development will benefit from the vast resources at UCLA, a world-renowned research university. The research plan aims to investigate the regulation of bioactive FGF23 concentrations by erythropoietin, iron, and phosphate, as well as the modulating effect of CKD on FGF23 bioactivity. Specific Aim 1 seeks to investigate the mechanisms by which erythropoietin affects bone Fgf23 expression. In mice with normal and impaired kidney function, Dr. Hanudel will examine how treatment with erythropoiesis stimulating agents affects bone Fgf23 expression and circulating FGF23 levels, and explore the mechanisms that mediate these effects. Specific Aim 2 seeks to investigate the mechanisms by which erythropoietin, iron, phosphate, and CKD affect FGF23 cleavage mechanisms. This project seeks to provide important mechanistic insights regarding the novel association between iron deficiency anemia and FGF23 in CKD. With this work, Dr. Hanudel aims to advance our knowledge of the intersection between CKD-associated anemia and CKD-MBD, potentially improving current CKD therapeutic strategies.

项目总结/摘要 该提案概述了儿科肾病学家Mark Hanudel博士的4年职业发展计划 开始了作为一名物理学家兼科学家的学术生涯。该计划旨在帮助他发展成为一个 FGF 23代谢领域最前沿的独立和多产的科学研究人员，以及 最终在慢性肾脏疾病-矿物质骨障碍（CKD-MBD）的其他方面。FGF 23是一种骨- 衍生的磷酸尿激素，其水平在CKD早期增加，并与不利的“关闭”有关。 目标”效应，包括总体死亡率增加、心血管发病率增加和发展 心室肥大FGF 23的生理调节是复杂的、多方面的，并且仍然不完全。 明白除了矿物质代谢因素，缺铁和促红细胞生成素已被证明， 影响FGF 23的产生和代谢。由于缺铁性贫血和促红细胞生成素的使用非常 在CKD人群中很常见，这些FGF 23的新决定因素特别相关，值得研究。 进一步研究了解铁和促红细胞生成素如何影响FGF 23可能会导致新的CKD治疗 旨在降低CKD相关心血管发病率和死亡率的策略。 博士Hanudel将受益于与他的主要导师，托马斯甘茨博士，在该领域的领导者密切互动 和Isidro Salusky博士，矿物质代谢和CKD领域的领导者。 通过加州大学洛杉矶分校的临床和转化科学研究所（CTSI）和儿童的发现和创新 研究所（CDI），哈努德尔博士将有机会获得许多职业发展研讨会，解决这些 主题为赠款写作，手稿准备和伦理研究。他将攻读研究生课程， 他还将继续接受分子生物学方面的培训，并将完成临床科学硕士学位并进行答辩。 研究论文，进一步加强他的生物统计学训练。哈努德尔博士得到了他所在机构的全力支持， 职业发展将受益于加州大学洛杉矶分校，一个世界著名的研究型大学的巨大资源。 该研究计划旨在研究促红细胞生成素，铁， 以及CKD对FGF 23生物活性的调节作用。具体目标1： 研究促红细胞生成素影响骨Fgf 23表达的机制。在正常和 肾功能受损，Hanudel博士将研究如何治疗红细胞生成刺激剂 影响骨FGF 23表达和循环FGF 23水平，并探索介导这些的机制。 方面的影响.具体目标2旨在研究促红细胞生成素、铁、磷酸盐和CKD的机制， 影响FGF 23裂解机制。该项目旨在提供重要的机械见解， CKD患者缺铁性贫血与FGF 23之间的新关联。通过这项工作，Hanudel博士旨在 推进我们对CKD相关贫血和CKD-MBD之间交叉的认识， 改善目前的CKD治疗策略。