Therapeutic potential of HIF-PHDi in the control of bioactive FGF23 in CKD.

项目摘要/摘要：NRSA为Noonan女士量身定做的这份提案提供了高质量的博士前 研究、培训和职业发展都围绕着她未来的目标。赞助商的优秀指导 记录，与领先的骨骼和肾脏生物医学研究人员的合作，以及卓越的环境 在IUSM和印第安纳州肌肉骨骼健康中心(ICMH)的工作将有助于成功完成 这个项目的。此外，参与未来教师和专业人员的道德准备方案 并资助写作课程、手稿准备、部门研讨会和期刊俱乐部，以及国家 会议将加强努南女士的职业发展，使她成为一个全面、独立的人 调查员。赞助者的实验室和其他实验室之前的研究已经确定了功能的获得和丧失 导致严重代谢性骨病的成纤维细胞生长因子-23(FGF23)突变， FGF23作为一种对磷酸盐代谢起中心作用的激素。FGF23是常见疾病中的一个重要因素。 改变的磷酸盐处理，如慢性肾脏疾病-矿物质和骨骼疾病(CKD-MBD)，具有高 循环浓度与患者死亡率相关。尽管在理解方面取得了进展 CKD-MBD中磷酸盐处理的基本和临床方面，调控FGF23的调节机制- 依赖的磷酸盐动态平衡仍然不清楚。重要的是，慢性肾脏病中会出现贫血，因为肾脏失去了 有能力产生促红细胞生成素(EPO)，许多患者接受EPO替代治疗。慢性肾脏病的贫血可以 由于肾脏促红细胞生成素合成不足、缺铁和/或促红细胞生成素抵抗，因此 磷酸盐和铁的处理可能对患者的治疗有重要影响。事实上，贫血和 外源性促红细胞生成素与慢性肾脏病预后不良有关，因此目前正在临床使用的一类新药 试验中，开发了低氧诱导因子Pro羟化酶抑制剂(HIF-PHDI)。这些类比 稳定HIF转录因子以刺激内源性EPO的产生，潜在地减少贫困 与肠外促红细胞生成素相关的结局。我们的初步结果有力地支持了HIF之间的新的相互作用。 PHDI和FGF23的表达。因此，这一提议将检验核心假设：FGF23受到直接刺激 通过临床相关的HIF-PHDI在成骨细胞/骨细胞中表达，其特定的衍生物对 生物活性FGF23的生产。在目标1中，HIF-PHDI介导的FGF23的分子机制 生产和稳定性将在体外测试；在目标2中，依赖于FGF23的矿物质效应 我们将研究HIF-PHDI在CKD-MBD小鼠模型中的代谢。使用这些 Noonan女士将在基因靶向和利用翻译模型方面获得新的研究技能 代谢性骨病。总的来说，这项提案将提供出色的研究、伦理以及书面和口头 对努南女士进行演讲培训，并测试导致内分泌的重要疾病机制 矿物质代谢紊乱。

Project Summary/Abstract: This NRSA proposal, tailored to Ms. Noonan, provides high quality predoctoral research training and career development centered upon her future goals. The sponsor’s excellent mentoring record, collaborations with leading bone and kidney biomedical researchers, and the outstanding environment at the IUSM and Indiana Center for Musculoskeletal Health (ICMH) will contribute to the successful completion of this project. Additionally, participation in the Preparing Future Faculty and Professionals program for ethics and grant writing courses, manuscript preparation, departmental seminars and journal clubs, as well as national meetings will enhance Ms. Noonan’s career development towards becoming a well-rounded, independent investigator. Previous studies from the sponsor’s lab and others have identified gain- and loss of function mutations in Fibroblast growth factor-23 (FGF23) that resulted in severe metabolic bone diseases, placing FGF23 as a hormone central to phosphate metabolism. FGF23 is an important factor in common diseases of altered phosphate handling such as chronic kidney disease-mineral and bone disorder (CKD-MBD), with high circulating concentrations associated with patient mortality. Although progress has been made in understanding basic and clinical aspects of phosphate handling in CKD-MBD, the regulatory mechanisms governing FGF23- dependent phosphate homeostasis remain unclear. Importantly, anemia arises in CKD as the kidneys lose the ability to produce erythropoietin (EPO), and many patients receive EPO replacement. The anemia of CKD can be due to lack of renal EPO synthesis, iron deficiency, and/or EPO resistance, thus cross talk between phosphate and iron handling may have important implications for patient treatment. Indeed, both anemia and exogenous EPO are associated with poor outcomes in CKD, therefore a novel class of drugs currently in clinical trials, Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHDi) were developed. These analogs stabilize HIF transcription factors to stimulate production of endogenous EPO, potentially reducing poor outcomes associated with parenteral EPO. Our initial results strongly support novel interactions between HIF- PHDi and FGF23 expression. Thus, this proposal will test the central hypothesis: FGF23 is directly stimulated by clinically-relevant HIF-PHDi in osteoblasts/osteocytes, with specific derivatives having differing effects on bioactive FGF23 production. In Aim 1, the molecular mechanisms dictating HIF-PHDi mediated FGF23 production and stabilization will be tested in vitro; and in Aim 2, the FGF23-dependent effects on mineral metabolism following delivery of HIF-PHDi to a mouse model of CKD-MBD will be examined. Using these systems, Ms. Noonan will gain new research skills in gene targeting and utilizing translational models of metabolic bone diseases. Collectively, this proposal will provide excellent research, ethics, and written and oral presentation training to Ms. Noonan, as well as test important disease mechanisms that result in endocrine disturbances of mineral metabolism.