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Fibroblast Growth Factor 23 (FGF23) and It's Receptors

成纤维细胞生长因子 23 (FGF23) 及其受体

基本信息

批准号：
8721942
负责人：
jyothsna gattineni
金额：
$ 14.52万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721942
关键词：
Affect Affinity Aging Basic Science Bathing Binding Breeding Brush Border Chronic Kidney Failure Code Data Development Plans Disease Dose Enzymes Excretory function Exposure to FGFR1 gene FGFR3 gene FGFR4 gene Familial hypophosphatemic bone disease Family member Fibroblast Growth Factor Fibroblast Growth Factor Receptors Foundations Fracture Genes Goals Grant Growth Homeostasis Hormones Human Hypophosphatemia In Vitro Individual Injury Inorganic Phosphate Transporter Integral Membrane Protein K-Series Research Career Programs Kidney Kidney Calculi Knockout Mice Ligands Mentors Minor Mixed Function Oxygenases Mus Mutant Strains Mice Patients Phenotype Phosphorus Physicians Play Program Development RNA Splicing Regulation Research Research Personnel Resistance Rickets Risk Role Scientist Serum Serum Phosphorus Level Signal Transduction Specificity Techniques Testing Training Training Programs Transgenic Mice United States National Institutes of Health Variant Vitamin D Wild Type Mouse career career development design fibroblast growth factor 23 in vivo innovation inorganic phosphate insight mortality mouse model novel prevent public health relevance receptor receptor binding response sodium phosphate sodium-phosphate cotransporter proteins symporter

项目摘要

DESCRIPTION (provided by applicant): This NIH mentored Career Development Award proposal describes a five year training program for the development of an academic career of a physician scientist and to facilitate the transition to an independent investigator. To accomplish these goals, the candidate and her mentors have developed an integrated plan including innovative scientific ideas, advanced training in the field of basic science research and a detailed career development plan. This research will focus on elucidating FGF23 causes decreased phosphate reabsorption from the kidney by decreasing the expression of phosphate transporter in the proximal tubule. In addition, FGF23 decreases synthesis of 1,25 vitamin D in the proximal tubule. The receptors responsible for these different actions of FGF23 are unknown. It is known that the FGF family members bind to four fibroblast growth factor receptors (FGFRs) designated as FGFR1-4. FGFR1, FGFR3 and FGFR4 are present in the proximal tubule where the majority of phosphorus is reabsorbed. A recent in vivo study using FGFR null mice indicates that FGFR1 is the predominant receptor with FGFR4 playing a minor role in regulating the phosphate transporters in the proximal tubule, but baseline phosphate homeostasis remains normal in these FGFR null mice. This grant proposes that compensatory mechanisms exist at baseline in individual FGFR-/- mice and FGFR1-/-FGFR4-/- double mutant mice will have high serum phosphate levels at baseline and have resistance to FGF23. To test this hypothesis, FGFR1-/-FGFR4-/- mice will be generated and characterized, and the effects of FGF23 will be examined. Regulation of 1,25 vitamin D appears to be different from the regulation of sodium phosphate cotransporters with individual FGFR null mice showing significant decrease in the serum levels of 1,25 vitamin D on exposure to pharmacological doses of FGF23. To study the regulation of 1,25 vitamin D, different combinations of FGFR null mice will be examined for the effects of FGF23 on serum levels of 1,25 vitamin D. This grant also hypothesizes that Klotho, an essential co-factor for the actions of FGF23 can act as an independent phosphate regulating hormone, and it interacts with FGFRs to regulate phosphate homeostasis. To test this hypothesis, the effects of Klotho on phosphate homoeostasis will be studied in the various FGFR null mice. In humans, high FGF23 levels result in disturbances in phosphate homeostasis with hypophosphatemia and low 1,25 Vitamin D levels resulting in rickets, bone fractures and poor growth. High levels of FGF23 have also been associated with increased risk of mortality in patients with chronic kidney disease. Identifying the receptors for FGF23 will provide insights in to the mechanisms of actions of FGF23 and provide foundation for designing novel therapies to prevent the effects of FGF23.

描述（由申请人提供）：这个由NIH指导的职业发展奖提案描述了一个为期五年的培训计划，用于医生科学家的学术生涯的发展，并促进向独立研究者的过渡。为了实现这些目标，候选人和她的导师制定了一个综合计划，包括创新的科学思想，基础科学研究领域的高级培训和详细的职业发展计划。本研究将着重阐明FGF 23通过降低近曲小管中磷酸盐转运蛋白的表达来降低肾脏对磷酸盐的重吸收。此外，FGF 23减少近端小管中1，25维生素D的合成。负责FGF 23的这些不同作用的受体是未知的。已知FGF家族成员与四种被命名为FGFR 1 -4的成纤维细胞生长因子受体（FGFR）结合。FGFR 1、FGFR 3和FGFR 4存在于近端小管中，其中大部分磷被重吸收。最近使用FGFR缺失小鼠的体内研究表明，FGFR 1是主要受体，FGFR 4在调节近端小管中的磷酸盐转运蛋白中起次要作用，但基线磷酸盐稳态在这些FGFR缺失小鼠中保持正常。该资助提出，在个体FGFR-/-小鼠中存在基线补偿机制，并且FGFR 1-/-FGFR 4-/-双突变小鼠在基线时将具有高血清磷酸盐水平并且对FGF 23具有抗性。为了检验这一假设，将产生并表征FGFR 1-/-FGFR 4-/-小鼠，并将检查FGF 23的作用。1，25维生素D的调节似乎与磷酸钠共转运蛋白的调节不同，其中个体FGFR缺失小鼠在暴露于药理剂量的FGF 23时显示1，25维生素D的血清水平显著降低。为了研究1，25维生素D的调节，将检查FGFR缺失小鼠的不同组合的FGF 23对1，25维生素D的血清水平的影响。这项授权还假设Klotho是FGF 23作用的重要辅助因子，可以作为一种独立的磷酸盐调节激素，它与FGFR相互作用以调节磷酸盐稳态。为了检验这一假设，将在各种FGFR缺失小鼠中研究Klotho对磷酸盐体内平衡的影响。在人类中，高FGF 23水平导致磷酸盐体内平衡紊乱，伴有低磷酸盐血症，低1，25维生素D水平导致佝偻病、骨折和生长不良。高水平的FGF 23也与慢性肾病患者死亡风险增加有关。识别FGF 23的受体将为FGF 23的作用机制提供见解，并为设计新的治疗方法以预防FGF 23的作用提供基础。