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

描述（由申请人提供）：本提案旨在培养申请人从博士后到独立研究者的过渡技能。申请人已完成住院医师和临床研究员培训在内科和内分泌学作为UT西南医师科学家培训计划的成员。他计划扩大自己的科学技能，以实现成为一名医生兼科学家的事业。该提案的目的是为了科学发现，以及在广度和深度上增加申请人的荣誉。他将研究成纤维细胞生长因子（FGF） 15及其人类同源物FGF19 (FGF15/19)，前者因其调节胆汁酸和能量代谢而闻名，其在磷酸盐代谢中的潜在作用。这将建立一种新的候选肠肾轴介质。申请人的导师，博士。David Mangelsdorf和Steven Kliewer非常适合指导申请人进行这个项目，因为他们是研究内分泌FGF激素的世界知名专家。他们过去成功地培养了许多博士后，实现了科学独立。这个指导团队是由共同导师Orson Moe博士提出的能量和矿物质代谢界面研究的完美补充，Orson Moe博士是一位转化科学家，也是磷酸盐代谢领域无可争议的领导者。作为博士后培训生的导师，他也有着非常出色的记录。一个由三名杰出的内科科学家组成的咨询委员会将在科学和职业事务方面提供额外的支持和指导。申请人将研究肠源性激素FGF15/19作为餐后磷酸盐排泄肠肾轴的第一内分泌因子的影响。目的1将确定磷酸盐对小鼠和人类FGF15/19分泌的影响以及FGF15/19对肾脏磷酸盐运输的影响。目的2将确定在肾脏中介导FGF15/19 - FGF受体4和γ-Klotho作用的候选受体和共受体。综上所述，这些研究将证明或反驳FGF15/19是餐后激素，通过作用于肾脏FGFR4/γ-Klotho构成磷酸盐稳态肠肾轴的假设。这些研究有望扩大我们对磷酸盐稳态的生理和病理生理的认识，并为磷酸盐过量的治疗开辟新的途径。

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.