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

HIF-PHDi 在控制 CKD 中生物活性 FGF23 方面的治疗潜力。

基本信息

批准号：
10210261
负责人：
Megan Noonan
金额：
$ 2.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-05-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210261
关键词：
Adenine Affinity Anemia Animal Model Biochemistry Bone Diseases Cell Line Cell model Cells Chronic Kidney Failure Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Data Diet Disease Disease model Dose Educational Status Endocrine Endocrine System Diseases Environment Equilibrium Erythropoietin Ethics Familial hypophosphatemic bone disease Fellowship Foundations Functional disorder Future Future Teacher Gene Targeting Genes Goals Grant HIF1A gene Health Homeostasis Hormones Human Hypoxia Hypoxia Inducible Factor Indiana Individual Injections Iron Iron deficiency anemia Journals Kidney Laboratories Late-Onset Disorder Lead Manuscripts Mediating Mendelian disorder Mentors Metabolic Bone Diseases Metabolism Minerals Modeling Molecular Mus Musculoskeletal National Research Service Awards Oral Osteoblasts Osteocytes Outcome Pathogenesis Patient-Focused Outcomes Patients Pregnancy Preparation Procollagen-Proline Dioxygenase Production Protein Isoforms Proteolytic Processing Puberty Regulatory Pathway Renal clearance function Replacement Therapy Research Research Ethics Research Personnel Research Training Resistance Rodent Model Scientist Serum Solid Sum System Techniques Testing Therapeutic Training Treatment Protocols Work Writing analog base bone career career development clinically relevant experimental study fibroblast growth factor 23 gain of function mutation in vitro testing inhibitor/antagonist innovation inorganic phosphate iron deficiency loss of function mutation meetings mortality mouse model new therapeutic target novel novel drug class optimal treatments patient population pre-doctoral programs response skeletal disorder skills transcription factor translational model treatment strategy wasting

项目摘要

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.

项目摘要/摘要：这项 NRSA 提案专为 Noonan 女士量身定制，提供高质量的博士前课程研究培训和职业发展以她未来的目标为中心。记录、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 IUSM 和印第安纳肌肉骨骼健康中心 (ICMH) 将为成功完成做出贡献此外，还参与了“为未来教师和专业人员做好道德准备”计划。和资助写作课程、手稿准备、部门研讨会和期刊俱乐部以及国家会议将促进努南女士的职业发展，使其成为一名全面、独立的人申办者实验室和其他人之前的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 (FGF23) 突变导致严重的代谢性骨病， FGF23作为磷酸盐代谢的核心激素，是常见疾病的重要因素。改变磷酸盐处理，例如慢性肾病-矿物质和骨病（CKD-MBD），尽管在理解方面已取得进展，但循环浓度与患者死亡率相关。 CKD-MBD 中磷酸盐处理的基本和临床方面，控制 FGF23- 的调节机制重要的是，CKD 患者会因肾脏失去磷酸盐而出现贫血。产生促红细胞生成素 (EPO) 的能力，许多患者接受 EPO 替代治疗可以缓解 CKD 贫血。是由于肾脏 EPO 合成不足、缺铁和/或 EPO 抵抗所致，因此事实上，磷酸盐和铁的处理可能对患者的治疗产生重要影响。外源性 EPO 与 CKD 的不良预后相关，因此目前临床上有一类新型药物试验中，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。 HIF 稳定转录因子，刺激内源性 EPO 的产生，可能减少不良反应我们的初步结果强烈支持 HIF- 之间的新相互作用。 PHDi 和 FGF23 表达因此，该提案将检验中心假设：FGF23 被直接刺激。通过成骨细胞/骨细胞中临床相关的 HIF-PHDi，特定衍生物对生物活性 FGF23 的产生在目标 1 中，决定 HIF-PHDi 介导的 FGF23 的分子机制。将在体外测试 FGF23 的产生和稳定性；目标 2 将测试 FGF23 对矿物质的影响将使用这些检查将 HIF-PHDi 递送至 CKD-MBD 小鼠模型后的代谢。系统，努南女士将获得基因靶向和利用转化模型的新研究技能总的来说，该提案将提供出色的研究、伦理以及书面和口头的内容。为 Noonan 女士提供演讲培训，并测试导致内分泌失调的重要疾病机制矿物质代谢紊乱。