This three-year NRSA training plan tailored to Dr. Clinkenbeard provides high quality 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 outstanding environment will contribute to the successful completion of this project. Additionally, participation in the Preparing Future Faculty program for ethics and grant writing courses, departmental seminars and journal clubs, and national meetings will enhance Dr. Clinkenbeard'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), a hormone central to phosphate metabolism, resulted in severe metabolic bone diseases. FGF23 is also emerging as an important factor in common diseases of altered phosphate handling such as CKD-MBD, with associations to patient mortality, response to calcitrol therapy, and cardiac hypertrophy. A knock-in mouse expressing an FGF23 stabilizing mutation (R176Q) identified from autosomal dominant hypophosphatemia rickets (ADHR) patients was created to test relevant hypotheses regarding the control of this hormone. ADHR mice developed hypophosphatemia due to high circulating FGF23 when provided an iron deficient diet, similar to iron deficient states in ADHR patients. Importantly, anemia is present in over 70% of end stage renal failure patients concomitant with increased FGF23 and hyperphosphatemia, therefore this training will occur in an environment of providing potentially important impact for a severe, common disease with no cure. Our initial results strongly support novel interactions between the Hypoxia inducible factor (HIF) transcription factor family and FGF23 expression. We propose a mechanistic link between iron and phosphate metabolism through key cellular iron/hypoxia sensing responses that drive FGF23 expression. Thus, this proposal will test the central hypothesis: iron deficiency and tissue hypoxia elevate FGF23 through HIF-dependent mechanisms, leading to pathogenic disturbances in phosphate metabolism and severe endocrine bone disease.
In Aim 1, the molecular mechanisms underlying FGF23 expression will be tested during iron deficiency and repletion regimen using ADHR mice with bone-specific deletion of HIF1a and the HIF-suppressor VHL. The transcriptional mechanisms controlling FGF23 expression will be tested in Aim 2 using an in vitro approach examining FGF23 promoter mutations and direct actions of HIF1a. Using these systems, Dr. Clinkenbeard will gain skills in translational models of metabolic bone diseases that logically build upon her previous research experiences. Together, the two aims will provide excellent research training and contribute to understanding disease mechanisms that result in endocrine disturbances of mineral metabolism.
The regulation of serum phosphate concentrations is critical for normal skeletal formation and cellular function. Pathophysiologic disturbances in phosphate homeostasis, such as those in autosomal dominant hypophosphatemic rickets (ADHR) and hyperphosphatemic tumoral calcinosis (TC), or common disorders such as chronic kidney disease-mineral bone disorder (CKD-MBD), lead to severe hormonal and skeletal disease. We expect that our proposed studies will reveal new mechanisms involved in phosphate homeostasis, which will provide novel therapeutic targets.
|Clinkenbeard, Erica L; White, Kenneth E (2017) Heritable and acquired disorders of phosphate metabolism: Etiologies involving FGF23 and current therapeutics. Bone 102:31-39|
|Hum, Julia M; O'Bryan, Linda M; Tatiparthi, Arun K et al. (2017) Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho. J Am Soc Nephrol 28:1162-1174|
|Clinkenbeard, Erica L; Hanudel, Mark R; Stayrook, Keith R et al. (2017) Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica 102:e427-e430|
|Hum, Julia M; Clinkenbeard, Erica L; Ip, Colin et al. (2017) The metabolic bone disease associated with theHypmutation is independent of osteoblastic HIF1? expression. Bone Rep 6:38-43|
|Murali, Sathish K; Andrukhova, Olena; Clinkenbeard, Erica L et al. (2016) Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice. PLoS Biol 14:e1002427|
|Clinkenbeard, Erica L; White, Kenneth E (2016) Systemic Control of Bone Homeostasis by FGF23 Signaling. Curr Mol Biol Rep 2:62-71|
|Clinkenbeard, Erica L; Cass, Taryn A; Ni, Pu et al. (2016) Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Miner Res 31:1247-57|
|Fleet, James C; Replogle, Rebecca A; Reyes-Fernandez, Perla et al. (2016) Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice. Endocrinology 157:470-81|