FGF15/FGF19 - γ Klotho FGFR axis in renal phosphate homeostasis

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DESCRIPTION (provided by applicant): This proposal is designed to develop the applicant's skills for transition from postdoctoral fellow to independent investigator. The applicant has completed residency and clinical fellowship training in internal medicine and endocrinology as a member of the Physician Scientist Training Program at UT Southwestern. He plans to expand his scientific skills to achieve a career as physician-scientist. The objectives of this proposal ae designed for scientific discovery, as well as growth of the applicant's accolades in breadth and in depth. He will study fibroblast growth factor (FGF) 15 and its human ortholog FGF19 (FGF15/19), previously known for its regulation of bile acid and energy metabolism, for its potential role in phosphate metabolism. This will establish a novel candidate mediator of the intestinal-renal axis. The applicant's mentors, Drs. David Mangelsdorf and Steven Kliewer, are perfectly suited for supervising the applicant on this project, as they are world-renowned experts for the study of endocrine FGF hormones. They have successfully trained numerous postdoctoral fellows in the past to achieve scientific independence. This mentoring team is perfectly complemented for the proposed studies at the interface between energy and mineral metabolism by co-mentor Dr. Orson Moe, who is a translational scientist and an undisputed leader in the field of phosphate metabolism. He also has a very strong track record as mentor of postdoctoral trainees. An advisory committee consisting of three outstanding physician-scientists will provide additional support and guidance in scientific and career matters. The applicant will examine the effects of the gut-derived hormone FGF15/19 as the first endocrine factor for the intestinal- renal axis of postprandial phosphate excretion. Aim 1 will define the effect of phosphate on FGF15/19 secretion and the effect of FGF15/19 on renal phosphate transport in mice and humans. Aim 2 will define the proposed candidate receptor and co-receptor in the kidney that transduce the effects of FGF15/19 - FGF receptor 4 and γ-Klotho. Together, these studies will prove or refute the hypothesis that FGF15/19 is the postprandial hormone that constitutes the intestinal-renal axis of phosphate homeostasis via acting on renal FGFR4/γ-Klotho. These studies have the prospect to expand our understanding of the physiology and pathophysiology of phosphate homeostasis and open up novel avenues for therapy of phosphate excess.