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: 7961038
• 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/7961038
• 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，以开发医师科学家的学术生涯，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项综合计划，包括创新的科学思想，基础科学研究领域的高级培训以及详细的职业发展计划。这项研究将集中于阐明FGF23，从而通过降低近端小管中磷酸转运蛋白的表达来降低肾脏的磷酸盐重吸收。另外，FGF23降低了近端小管中1,25个维生素D的合成。负责FGF23的这些不同作用的受体尚不清楚。众所周知，FGF家族成员与指定为FGFR1-4的四个成纤维细胞生长因子受体（FGFR）结合。 FGFR1，FGFR3和FGFR4存在于大多数磷被重吸收的近端小管中。最近使用FGFR无效小鼠的体内研究表明，FGFR1是FGFR4的主要受体，在调节近端小管中的磷酸转运蛋白方面发挥了较小的作用，但是这些FGFR NULL小鼠中的基线磷酸盐稳态仍然正常。该赠款提出，在单个FGFR - / - 小鼠和FGFR1 - / - FGFR4 - / - 双重突变小鼠的基线中存在补偿机制在基线时具有高血清磷酸盐水平，并且对FGF23具有抗性。为了检验该假设，将生成和表征FGFR1 - / - FGFR4 - / - 小鼠，将检查FGF23的效果。 1,25维生素D的调节似乎与对磷酸钠共转运蛋白的调节不同，其单个FGFR无效小鼠在暴露于药理学剂量的FGF23时，血清1,25维生素D的血清水平显着降低。为了研究1,25个维生素D的调节，将检查FGFR NULL小鼠的不同组合，以了解FGF23对1,25维生素D的血清水平的影响D。该拨款还假设Klotho是FGF23的作用Klotho，是FGF23的作用的必不可少的辅助因素，可以与磷酸盐调节型磷酸盐相互作用。为了检验这一假设，将研究克洛索对磷酸盐同构的影响。在人类中，高FGF23水平导致低磷酸血症和低1,25个维生素D水平导致磷酸盐稳态的障碍，导致rick骨，骨折和生长不佳。高水平的FGF23也与慢性肾脏疾病患者死亡风险增加有关。识别FGF23的受体将提供有关FGF23作用机理的见解，并为设计新型疗法提供基础，以防止FGF23的影响。 公共卫生相关性：高水平的FGF23患者的r子，生长差，骨折风险增加以及缺乏治疗疗法。当前的疗法导致肾结石和进行性肾脏损伤。 FGF23的特定受体的鉴定将有助于设计特定的受体拮抗剂，从而提供治疗方法。