Role of iron and hypoxia sensing in FGF23-dependent metabolic bone disease

铁和缺氧传感在 FGF23 依赖性代谢性骨病中的作用

基本信息

批准号：
8850699
负责人：
Erica L Clinkenbeard
金额：
$ 6.05万
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：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850699
关键词：
Address Adult Anemia Binding Biological Bone Diseases Calcinosis Cell physiology Chronic Kidney Failure Clinical Collaborations Comorbidity Complex Dialysis procedure Diet Disease Disease Progression Elements End stage renal failure Endocrine Endocrine Bone Diseases Environment Erythropoietin Ethics Etiology Faculty Familial hypophosphatemic bone disease Family Future Genes Goals Grant Heart Hypertrophy Hematocrit procedure Homeostasis Hormonal Hormones Hypophosphatemia Hypoxia Hypoxia Inducible Factor In Vitro Individual Iron Journals Kidney Kidney Diseases Knock-in Mouse Late-Onset Disorder Lead Light Link Mentors Messenger RNA Metabolic Bone Diseases Metabolism Minerals Modeling Molecular Mus Mutation National Research Service Awards Patients Pregnancy Process Production Protein Isoforms Proteins Puberty Regimen Regulation Research Research Personnel Research Training Resistance Response Elements Rickets Role Serum Staging Syndrome System Testing Time Tissues Training Transcriptional Regulation Wild Type Mouse Withdrawal Work Writing bone career development experience fibroblast growth factor 23 gain of function mutation hypoxia inducible factor 1 in vivo inorganic phosphate iron deficiency loss of function mutation meetings mortality mouse model new therapeutic target novel pediatric patients programs promoter public health relevance response skeletal skeletal disorder skills transcription factor wasting

项目摘要

DESCRIPTION (provided by applicant): This three-year NRSA training plan tailored to Dr. Clinkenbeard provides high quality 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 outstanding environment will contribute to the successful completion of this project. Additionally, participation in the Preparing Future Faculty program for ethics and grant writing courses, departmental seminars and journal clubs, and national meetings will enhance Dr. Clinkenbeard'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), a hormone central to phosphate metabolism, resulted in severe metabolic bone diseases. FGF23 is also emerging as an important factor in common diseases of altered phosphate handling such as CKD-MBD, with associations to patient mortality, response to calcitrol therapy, and cardiac hypertrophy. A knock-in mouse expressing an FGF23 stabilizing mutation (R176Q) identified from autosomal dominant hypophosphatemia rickets (ADHR) patients was created to test relevant hypotheses regarding the control of this hormone. ADHR mice developed hypophosphatemia due to high circulating FGF23 when provided an iron deficient diet, similar to iron deficient states in ADHR patients. Importantly, anemia is present in over 70% of end stage renal failure patients concomitant with increased FGF23 and hyperphosphatemia, therefore this training will occur in an environment of providing potentially important impact for a severe, common disease with no cure. Our initial results strongly support novel interactions between the Hypoxia inducible factor (HIF) transcription factor family and FGF23 expression. We propose a mechanistic link between iron and phosphate metabolism through key cellular iron/hypoxia sensing responses that drive FGF23 expression. Thus, this proposal will test the central hypothesis: iron deficiency and tissue hypoxia elevate FGF23 through HIF-dependent mechanisms, leading to pathogenic disturbances in phosphate metabolism and severe endocrine bone disease. In Aim 1, the molecular mechanisms underlying FGF23 expression will be tested during iron deficiency and repletion regimen using ADHR mice with bone-specific deletion of HIF1a and the HIF-suppressor VHL. The transcriptional mechanisms controlling FGF23 expression will be tested in Aim 2 using an in vitro approach examining FGF23 promoter mutations and direct actions of HIF1a. Using these systems, Dr. Clinkenbeard will gain skills in translational models of metabolic bone diseases that logically build upon her previous research experiences. Together, the two aims will provide excellent research training and contribute to understanding disease mechanisms that result in endocrine disturbances of mineral metabolism.

描述（由申请人提供）：这项为Clinkenbeard博士量身定制的三年NRSA培训计划提供了以她未来目标为中心的高质量研究培训和职业发展。赞助商的出色指导记录，与领先的骨骼和肾脏生物医学研究人员的合作以及出色的环境将有助于成功完成该项目。此外，参加准备未来的教师计划道德和赠款写作课程，部门研讨会和期刊俱乐部以及全国会议将增强Clinkenbeard博士的职业发展发展，成为一名全面的独立调查员。赞助商实验室和其他人的先前研究已经确定了成纤维细胞生长因子23（FGF23）中功能突变的增益和丧失，这是一种磷酸代谢中心的激素，导致严重的代谢骨疾病。 FGF23还成为改变磷酸盐处理（例如CKD-MBD）的常见疾病的重要因素，与患者死亡率有关，对钙酚治疗的反应和心脏肥大。创建了一种表达从常染色体显性低磷酸盐rike（ADHR）患者中鉴定出的FGF23稳定突变（R176Q）的敲入小鼠，以检验有关该激素对照的相关假设。 ADHR小鼠在提供铁不足的饮食时，由于高循环的FGF23而导致低磷酸血症，类似于ADHR患者的铁不足状态。重要的是，超过70％的末期肾衰竭患者与FGF23和高磷酸血症有关，贫血存在于70％以上，因此，这种训练将发生在为无法治愈的严重，常见疾病提供潜在重要影响的环境中。我们的最初结果强烈支持缺氧诱导因子（HIF）转录因子家族和FGF23表达之间的新型相互作用。我们提出了通过驱动FGF23表达的钥匙细胞/缺氧感应反应，提出了铁和磷酸盐代谢之间的机械联系。因此，该提案将检验中心假设：铁缺乏症和组织缺氧通过HIF依赖性机制升高FGF23，从而导致磷酸代谢和严重内分泌骨病的致病性干扰。在AIM 1中，使用具有HIF1A的骨特异性缺失和HIF-抑制剂VHL的ADHR小鼠，将测试FGF23表达的分子机制。控制FGF23表达的转录机制将在AIM 2中使用研究FGF23启动子突变和HIF1A的直接作用进行测试。使用这些系统，Clinkenbeard博士将在逻辑上以她以前的研究经历为基础的代谢骨骼疾病的翻译模型中获得技能。这两个目标共同提供了出色的研究培训，并有助于理解疾病机制，从而导致矿物质代谢的内分泌干扰。