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

项目摘要/摘要 这份提案为儿科肾病专家马克·哈努德尔医生勾勒出了4年职业发展计划。 作为一名内科科学家开始了他的学术生涯。该计划旨在帮助他发展成为一名 处于FGF23代谢领域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的其他方面-矿物性骨病(CKD-MBD)。FGF23是一块骨头- 衍生的磷酸尿激素，其水平在慢性肾脏病的早期升高，并与不良的“关”有关 目标“效应，包括总死亡率增加，心血管发病率增加，以及 心脏肥厚的症状。FGF23的生理调控是复杂的、多方面的，而且仍然不完全 明白了。除了矿物质代谢因素外，铁缺乏和促红细胞生成素已被证明是 影响FGF23的产生和代谢。由于缺铁性贫血和促红细胞生成素的使用过多 在CKD人群中很常见，这些FGF23的新决定因素尤其相关，值得研究 进一步研究。对铁和促红细胞生成素如何影响FGF23的洞察可能导致新的CKD治疗 旨在降低慢性肾脏病相关心血管发病率和死亡率的战略。 哈努德尔博士将受益于与他的主要导师、该领域的领军人物托马斯·甘茨博士的密切互动 Isidro Salusky博士是贫血和铁代谢领域的专家，他是矿物质代谢和慢性肾脏病领域的领导者。 通过加州大学洛杉矶分校的临床和翻译科学研究所(CTSI)和儿童的发现和创新 哈努德尔博士将有机会参加许多职业发展研讨会，解决这些问题 主题包括基金写作、手稿准备和伦理研究。他将参加研究生课程以获得 进一步接受分子生物学方面的培训，并将完成并捍卫他的临床理学硕士学位 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，他的 职业发展将受益于加州大学洛杉矶分校的巨大资源，这是一所世界知名的研究型大学。 该研究计划旨在研究促红细胞生成素、铁、铁对生物活性FGF23浓度的调节。 以及CKD对FGF23生物活性的调节作用。具体目标1旨在 探讨促红细胞生成素影响骨FGF23表达的机制。在正常和正常小鼠中 肾功能受损，Hanudel博士将研究如何使用促红细胞生成剂进行治疗 影响骨FGF23表达和循环FGF23水平，并探讨其调节机制 效果。特定目标2试图研究促红细胞生成素、铁、磷酸盐和慢性肾脏病的机制 影响FGF23的切割机制。该项目寻求提供关于以下方面的重要机械性见解 慢性肾脏病缺铁性贫血与FGF23的新关联。通过这项工作，哈努德尔博士的目标是 提高我们对CKD相关性贫血和CKD-MBD之间的交集的知识，潜在地 改进目前的慢性肾脏病治疗策略。

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.