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

项目概要/摘要：这NRSA的建议，为努南女士量身定制，提供高质量的博士预科 研究培训和职业发展集中在她的未来目标。赞助商的优秀指导 与领先的骨骼和肾脏生物医学研究人员的合作，以及出色的环境 在IUSM和印第安纳州肌肉骨骼健康中心（ICMH）的研究将有助于成功完成 of this project项目.此外，参加准备未来的教师和专业人员的道德方案， 和赠款写作课程，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，成为一个全面的，独立的， 调查员来自申办者实验室和其他实验室的先前研究已经确定了功能的获得和丧失 成纤维细胞生长因子-23（FGF 23）突变导致严重的代谢性骨病， FGF 23作为磷酸盐代谢的核心激素。FGF 23是一个重要的因素，在常见的疾病， 磷酸盐处理改变，如慢性肾脏疾病-矿物质和骨疾病（CKD-MBD）， 与患者死亡率相关的循环浓度。尽管在理解方面取得了进展， CKD-MBD中磷酸盐处理的基础和临床方面，控制FGF 23- 依赖磷酸盐的体内平衡仍不清楚。重要的是，CKD患者出现贫血，因为肾脏失去了 产生促红细胞生成素（EPO）的能力，许多患者接受EPO替代。CKD的贫血可以 可能是由于缺乏肾EPO合成、铁缺乏和/或EPO抗性，因此 磷酸盐和铁的处理可能对患者治疗有重要意义。事实上，贫血和 外源性EPO与CKD的不良结局相关，因此是目前临床上使用的一类新药物。 试验中，开发了缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHDi）。这些类似物 稳定HIF转录因子以刺激内源性EPO的产生，潜在地减少不良的 与肠外EPO相关的结局。我们的初步结果强烈支持HIF-1 α之间的新的相互作用。 PHDi和FGF 23表达。因此，该提议将测试中心假设：FGF 23被直接刺激 通过成骨细胞/骨细胞中的临床相关HIF-PHDi，特定衍生物对 生物活性FGF 23的产生。在目标1中，HIF-PHDi介导的FGF 23的分子机制 将在体外测试FGF 23的产生和稳定性;在目标2中，将测试FGF 23对矿物质的依赖性作用。 将检查HIF-PHDi递送至CKD-MBD小鼠模型后的代谢。使用这些 系统，努南女士将获得新的研究技能，在基因靶向和利用翻译模型， 代谢性骨病总的来说，这项提案将提供优秀的研究，道德，书面和口头 介绍培训努南女士，以及测试重要的疾病机制，导致内分泌 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.