In the early stages of my fellowship training in nephrology, I began working with Dr. Darryl Quarles to investigate the role of fibroblast growth factor 23 (FGF23) in phosphate and vitamin D homeostasis. Since these early days in the lab, mineral metabolism has remained my primary area of interest, and I have developed a clear vision of my long-term research and career goals within this field. My career plan is to become a successful independent investigator using basic science methodology to perform translational research aimed at defining the role of aberrant mineral metabolism as a contributor to the co-morbidities associated with progressive kidney disease. I believe the time I have dedicated to performing bench research, combined with the knowledge I have gained through my previous work investigating the role of FGF23 in mineral metabolism, has laid the groundwork for the realization of this long-term goal. There is emerging evidence that FGF23 is important in the pathogenesis of chronic kidney disease-mineral and bone disorder (CKD-MBD). The preliminary work that I have outlined in this application has focused on defining the pathogenesis of CKD-MBD in the context of FGF23 regulation and function. We postulate that early increments of FGF23 from bone are an inciting event which contributes to the development of mineral metabolism abnormalities in this setting. We believe that CKD does not represent a true """"""""vitamin D deficient"""""""" state resulting from renal injury, rather suppression of 1,25(OH)2D production by elevated FGF23 is an adaptive response to maintain neutral phosphate balance in the setting of progressive nephron loss. To elucidate the regulation and function of FGF23 in CKD, we have obtained a genetically altered mouse model of CKD (Col4a3 null mouse) and extensively characterized the bone and mineral metabolism phenotype of this model. Our findings thus far have supported the use of this mouse strain as a model of CKD-MBD found in humans. In this model, mineral metabolism pathways can be altered in a controlled environment to gain insight into the interrelationships and tissue specific effects of individual mineral metabolism pathways. In this proposal, we plan to investigate the impact of several interventions aimed at preventing the natural progression of mineral metabolism changes in CKD. Our specific manipulations will include: 1) the prevention of hyperphosphatemia with phosphate restriction, 2) early calcitriol therapy to counteract the progressive development of 1,25(OH)2D deficiency, 3) early calcimimetic therapy to prevent the development of secondary hyperparathyroidism, 4) the administration of FGF23-deactivating antibodies to lower active circulating FGF23 levels, and 5) the over-expression of klotho to prevent decrements in renal klotho expression. These studies will lead to new knowledge of a complex systems biology that has evolved to permit cross-talk between bone and kidney to coordinate phosphate balance, vitamin D metabolism and bone mineralization. Such knowledge will help us understand and better manage disordered mineral metabolism in patients with CKD.
Fibroblast growth factor 23 (FGF23) is a novel hormone that has been found to regulate phosphorus and vitamin D levels in the body, and it is extremely elevated in patients with kidney disease. The discovery of this hormone has changed our thinking regarding the origins of mineral metabolism abnormalities in patients with chronic kidney disease. We plan to use a mouse model of progressive kidney disease to investigate the complex interrelationships of mineral metabolism pathways and to identify the specific contributions of these pathways to the vascular and bone co-morbidities that are common in this setting. Project Narrative Fibroblast growth factor 23 (FGF23) is a novel hormone that has been found to regulate phosphorus and vitamin D levels in the body, and it is extremely elevated in patients with kidney disease. The discovery of this hormone has changed our thinking regarding the origins of mineral metabolism abnormalities in patients with chronic kidney disease. We plan to use a mouse model of progressive kidney disease to investigate the complex interrelationships of mineral metabolism pathways and to identify the specific contributions of these pathways to the vascular and bone co-morbidities that are common in this setting.
|Silswal, Neerupma; Touchberry, Chad D; Daniel, Dorothy R et al. (2014) FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab 307:E426-36|
|Touchberry, Chad D; Green, Troy M; Tchikrizov, Vladimir et al. (2013) FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 304:E863-73|
|Zhang, Shiqin; Gillihan, Ryan; He, Nan et al. (2013) Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease. Kidney Int 84:713-21|
|Stubbs, Jason R; He, Nan; Idiculla, Arun et al. (2012) Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease. J Bone Miner Res 27:38-46|