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

成纤维细胞生长因子 23 (FGF23) 及其受体

• 批准号: 8322841
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322841
• 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

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.

描述（由申请人提供）：这项 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，旨在发展医师科学家的学术职业并促进其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，包括创新的科学理念、基础科学研究领域的高级培训和详细的职业发展计划。这项研究将重点阐明 FGF23 通过降低近曲小管中磷酸盐转运蛋白的表达，导致肾脏磷酸盐重吸收减少。此外，FGF23 还可减少近曲小管中 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 FGF 家族成员与四种成纤维细胞生长因子受体 (FGFR) 结合，称为 FGFR1-4。 FGFR1、FGFR3 和 FGFR4 存在于近端肾小管中，大部分磷在此被重吸收。最近一项使用 FGFR 缺失小鼠的体内研究表明，FGFR1 是主要受体，FGFR4 在调节近端肾小管磷酸盐转运蛋白方面发挥次要作用，但这些 FGFR 缺失小鼠的基线磷酸盐稳态仍然正常。这项资助提出，个体 FGFR-/- 小鼠的基线存在补偿机制，而 FGFR1-/-FGFR4-/- 双突变小鼠的基线血清磷酸盐水平较高，并对 FGF23 具有抵抗力。为了检验这一假设，将生成 FGFR1-/-FGFR4-/- 小鼠并进行表征，并检查 FGF23 的影响。 1,25 维生素 D 的调节似乎与磷酸钠协同转运蛋白的调节不同，个别 FGFR 缺失小鼠表现出暴露于药理学剂量的 FGF23 后 1,25 维生素 D 的血清水平显着降低。为了研究 1,25 维生素 D 的调节，将检查不同组合的 FGFR 缺失小鼠中 FGF23 对 1,25 维生素 D 血清水平的影响。这项资助还假设 FGF23 作用的重要辅助因子 Klotho 可以充当独立的磷酸盐调节激素，并且它与 FGFR 相互作用以调节磷酸盐稳态。为了检验这一假设，我们将在各种 FGFR 缺失小鼠中研究 Klotho 对磷酸盐稳态的影响。在人类中，高 FGF23 水平会导致磷酸盐稳态紊乱，导致低磷血症，而 1,25 维生素 D 水平低则会导致佝偻病、骨折和生长不良。高水平的 FGF23 还与慢性肾病患者的死亡风险增加有关。鉴定 FGF23 受体将为了解 FGF23 的作用机制提供见解，并为设计预防 FGF23 影响的新疗法奠定基础。 公众健康相关性：FGF23 水平高的患者患有佝偻病、生长不良、骨折风险增加，并且缺乏治疗方法。目前的治疗会导致肾结石和进行性肾损伤。 FGF23特异性受体的鉴定将有助于设计特异性受体拮抗剂，从而提供治愈性治疗。