Therapeutic potential of HIF-PHDi in the control of bioactive FGF23 in CKD.

项目摘要/摘要：该NRSA提案为Noonan女士量身定制，提供高质量的博士预科课程

Project Summary/Abstract: This NRSA proposal, tailored to Ms. Noonan, provides high quality predoctoral research training and career development centered upon her future goals. The sponsor’s excellent mentoring record, collaborations with leading bone and kidney biomedical researchers, and the outstanding environment at the IUSM and Indiana Center for Musculoskeletal Health (ICMH) will contribute to the successful completion of this project. Additionally, participation in the Preparing Future Faculty and Professionals program for ethics and grant writing courses, manuscript preparation, departmental seminars and journal clubs, as well as national meetings will enhance Ms. Noonan’s career development towards becoming a well-rounded, independent investigator. Previous studies from the sponsor’s lab and others have identified gain- and loss of function mutations in Fibroblast growth factor-23 (FGF23) that resulted in severe metabolic bone diseases, placing FGF23 as a hormone central to phosphate metabolism. FGF23 is an important factor in common diseases of altered phosphate handling such as chronic kidney disease-mineral and bone disorder (CKD-MBD), with high circulating concentrations associated with patient mortality. Although progress has been made in understanding basic and clinical aspects of phosphate handling in CKD-MBD, the regulatory mechanisms governing FGF23- dependent phosphate homeostasis remain unclear. Importantly, anemia arises in CKD as the kidneys lose the ability to produce erythropoietin (EPO), and many patients receive EPO replacement. The anemia of CKD can be due to lack of renal EPO synthesis, iron deficiency, and/or EPO resistance, thus cross talk between phosphate and iron handling may have important implications for patient treatment. Indeed, both anemia and exogenous EPO are associated with poor outcomes in CKD, therefore a novel class of drugs currently in clinical trials, Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHDi) were developed. These analogs stabilize HIF transcription factors to stimulate production of endogenous EPO, potentially reducing poor outcomes associated with parenteral EPO. Our initial results strongly support novel interactions between HIF- PHDi and FGF23 expression. Thus, this proposal will test the central hypothesis: FGF23 is directly stimulated by clinically-relevant HIF-PHDi in osteoblasts/osteocytes, with specific derivatives having differing effects on bioactive FGF23 production. In Aim 1, the molecular mechanisms dictating HIF-PHDi mediated FGF23 production and stabilization will be tested in vitro; and in Aim 2, the FGF23-dependent effects on mineral metabolism following delivery of HIF-PHDi to a mouse model of CKD-MBD will be examined. Using these systems, Ms. Noonan will gain new research skills in gene targeting and utilizing translational models of metabolic bone diseases. Collectively, this proposal will provide excellent research, ethics, and written and oral presentation training to Ms. Noonan, as well as test important disease mechanisms that result in endocrine disturbances of mineral metabolism.