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

FGF15/FGF19 - 肾磷酸盐稳态中的 γ Klotho FGFR 轴

• 批准号: 9750017
• 负责人: Peter Gerhard Christoph Zechner
• 金额: $ 14.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750017
• 关键词: Advisory Committees; Affect; Agonist; American; Bile Acids; Binding; Blood Circulation; Calories; Cardiovascular system; Cell Culture Techniques; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Complement; Complex; Coupled; Culture Media; Data; Diabetes Mellitus; Endocrine; Endocrinology; Energy Intake; Energy Metabolism; Enterocytes; Evaluation; Evolution; Excretory function; FGF19 gene; FGFR4 gene; Family member; Fellowship; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Food; Functional disorder; Funding; General Population; Genetic Transcription; Growth; Homeostasis; Hormones; Hour; Human; In Vitro; Incubated; Ingestion; Injections; Inorganic Phosphate Transporter; Intake; Internal Medicine; Intestines; Kidney; Knockout Mice; Knowledge; Liver; Mediating; Mediator of activation protein; Mentors; Messenger RNA; Metabolism; Minerals; Morbidity - disease rate; Mus; Myocardial Infarction; Oral; Orthologous Gene; Patients; Physicians; Physiological; Physiology; Postdoctoral Fellow; Primary biliary cirrhosis; Protein Isoforms; Proteins; Proximal Kidney Tubules; Regulation; Research Personnel; Residencies; Rodent; Role; Scientist; Serum; Signal Transduction; Site; Stroke; Supervision; Training; Training Programs; Tubular formation; Urine; Variant; Wild Type Mouse; Work; bone; career; design; exosome; experimental study; fibroblast growth factor 23; fibroblast growth factor receptor 4; in vivo; inorganic phosphate; member; mortality; novel; paralogous gene; public health relevance; receptor; response; skills; translational scientist; urinary

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.

描述（由申请人提供）：本提案旨在培养申请人从博士后研究员过渡到独立研究员的技能。申请人已经完成了内科和内分泌学的住院医师和临床奖学金培训，成为UT西南部医师科学家培训计划的成员。他计划扩展他的科学技能，以实现作为物理学家科学家的职业生涯。本提案的目的是为了科学发现，以及申请人在广度和深度上的荣誉增长。他将研究成纤维细胞生长因子（FGF）15及其人类直系同源物FGF 19（FGF 15/19），以前已知其调节胆汁酸和能量代谢，其在磷酸盐代谢中的潜在作用。这将建立一个新的候选调解人的泌尿-肾轴。申请人的导师大卫曼格尔斯多夫博士和史蒂芬Kliewer，是非常适合监督申请人在这个项目上，因为他们是世界知名的专家研究内分泌FGF激素。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。这个指导团队是完美的补充，在能量和矿物质代谢之间的接口由共同导师奥森博士莫伊，谁是翻译科学家和磷酸盐代谢领域无可争议的领导者提出的研究。他也有一个非常强大的跟踪记录作为博士后学员的导师。一个由三位杰出的医生-科学家组成的咨询委员会将在科学和职业问题上提供额外的支持和指导。申请方将检查肠源性激素FGF 15/19作为餐后磷酸盐排泄的肠-肾轴的第一内分泌因子的作用。目的1将确定磷酸盐对FGF 15/19分泌的影响以及FGF 15/19对小鼠和人的肾磷酸盐转运的影响。目的2将确定肾脏中的候选受体和辅助受体，其证实FGF 15/19 - FGF受体4和γ-Klotho的作用。总之，这些研究将证明或反驳以下假设：FGF 15/19是餐后激素，其通过作用于肾FGFR 4/γ-Klotho构成磷酸盐稳态的肾-肾轴。这些研究具有前景，以扩大我们的理解的生理和病理生理的磷酸盐稳态和开辟新的途径，治疗磷酸盐过量。