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

点击翻译按钮获取中文摘要

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.