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

描述(由申请人提供)：这份由NIH指导的职业发展奖提案描述了一项为期五年的培训计划，旨在发展内科科学家的学术生涯，并促进向独立研究人员的过渡。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。本研究将集中于阐明FGF23通过减少近端小管磷酸转运蛋白的表达而导致肾脏磷酸盐重吸收减少的原因。此外，FGF23还减少了近端小管中1，25维生素D的合成。负责FGF23这些不同作用的受体尚不清楚。已知的是，成纤维细胞生长因子家族成员结合四个成纤维细胞生长因子受体(FGFRs)，命名为FGFR1-4。FGFR1、FGFR3和FGFR4存在于近端小管中，大部分磷被重新吸收。最近利用FGFR缺失小鼠进行的体内研究表明，FGFR1是主要的受体，FGFR4在调节近端小管的磷酸转运蛋白方面起次要作用，但这些FGFR缺失小鼠的基础磷酸盐稳态保持正常。这项资助提出，FGFR-/-小鼠个体的代偿机制存在于基线，FGFR1-/-FGFR4-/-双突变小鼠的血清磷水平在基线水平较高，并对FGF23具有抵抗力。为了验证这一假设，将产生并鉴定FGFR1-/-FGFR4-/-小鼠，并检验FGF23的作用。对1，25维生素D的调节似乎与对磷酸钠共转运体的调节不同，FGFR基因缺失的小鼠在暴露于药理剂量的FGF23后，血清1，25维生素D水平显著降低。为了研究1，25维生素D的调节，将检测FGF23对血清1，25维生素D水平的影响的不同FGFR缺失小鼠。这项研究还假设，Klotho是FGF23作用的基本辅助因素，可以作为一种独立的磷酸盐调节激素，它与FGFRs相互作用，调节磷酸盐稳态。为了验证这一假设，Klotho将在不同FGFR缺失的小鼠中研究Klotho对磷酸盐稳态的影响。在人类中，高水平的FGF23会导致低磷血症和低1，25维生素D水平的磷酸盐动态平衡紊乱，从而导致软骨病、骨折和生长不良。高水平的FGF23也与慢性肾脏疾病患者死亡风险的增加有关。识别FGF23的受体将有助于深入了解FGF23的作用机制，并为设计预防FGF23影响的新疗法提供基础。 与公共卫生相关：FGF23水平高的患者有软骨病、生长不良、骨折风险增加，并且缺乏治疗。目前的治疗方法会导致肾结石和进行性肾脏损伤。识别FGF23的特异性受体将有助于设计特异性受体拮抗剂，从而提供治疗。

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. PUBLIC HEALTH RELEVANCE: Patients with high levels of FGF23 have rickets, poor growth, and increased risk of fractures, and lack curative therapy. The current therapy results in kidney stones and progressive renal injury. The identification of specific receptors for FGF23 will help in designing specific receptor antagonists and thus provide curative treatment.