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

描述(由申请者提供)：本建议旨在培养申请者从博士后研究员过渡到独立研究员的技能。申请人已完成内科和内分泌学住院医师和临床研究员培训，成为德克萨斯大学西南分校内科科学家培训计划的一员。他计划扩展自己的科学技能，以实现内科科学家的职业生涯。这项提案的目的是为了科学发现，以及在广度和深度上提高申请人的荣誉。他将研究成纤维细胞生长因子15及其人类FGF19(FGF15/19)，此前以调节胆汁酸和能量代谢而闻名，因为它在磷酸盐代谢中可能发挥作用。这将建立一个新的肠道-肾轴的候选介体。申请人的导师David Mangelsdorf博士和Steven Kliewer博士非常适合在这个项目上监督申请人，因为他们是研究内分泌成纤维细胞生长因子激素的世界知名专家。他们在过去成功地培养了许多博士后研究员，以实现科学独立。这一指导团队与合作导师Orson Moe博士就能量和矿物质代谢之间的界面提出的研究进行了完美的补充，Orson Moe博士是一位翻译科学家，也是磷酸盐新陈代谢领域无可争议的领导者。作为博士后实习生的导师，他也有着非常出色的记录。一个由三位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上提供额外的支持和指导。申请者将研究肠源性激素FGF15/19作为餐后磷酸盐排泄的肠道-肾轴的第一个内分泌因子的影响。目的1确定磷酸盐对FGF15/19分泌的影响，以及FGF15/19对小鼠和人类肾脏磷酸盐转运的影响。目的2确定在肾脏中转导成纤维细胞生长因子15/19-成纤维细胞生长因子受体4和γ-Klotho效应的候选受体和辅助受体。总之，这些研究将证明或驳斥这样的假设，即FGF15/19是一种餐后激素，通过作用于肾脏FGFR4/γ-Klotho，构成肠-肾轴的磷酸盐稳态。这些研究有可能扩大我们对磷酸盐稳态的生理学和病理生理学的理解，并为治疗磷酸盐过量开辟新的途径。

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.