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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：
9055645
负责人：
Erica L Clinkenbeard
金额：
$ 6.45万
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/9055645
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 Familial hypophosphatemic bone disease Family Future Future Teacher Genes Goals Grant Health 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 overexpression pediatric patients programs promoter 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）：这个为期三年的NRSA培训计划为博士量身定制。Clinkenbeard提供高质量的研究培训和以她未来目标为中心的职业发展。赞助商优秀的指导记录，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本项目的成功完成。此外，参加准备未来教师计划，伦理和赠款写作课程，部门研讨会和期刊俱乐部，以及全国会议将加强博士Clinkenbeard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成纤维细胞生长因子-23（FGF 23）（一种对磷酸盐代谢起核心作用的激素）的功能突变的获得和丧失，导致严重的代谢性骨病。FGF 23也成为改变磷酸盐处理的常见疾病（如CKD-MBD）中的重要因素，与患者死亡率、对骨化醇治疗的反应和心脏肥大相关。建立了一种表达FGF 23稳定突变（R176 Q）的敲入小鼠，该突变从常染色体显性遗传低磷酸盐血症佝偻病（ADHR）患者中鉴定，以检验关于该激素控制的相关假设。当提供缺铁饮食时，ADHR小鼠由于高循环FGF 23而发生低磷酸盐血症，与ADHR患者的缺铁状态相似。重要的是，贫血存在于超过70%的终末期肾衰竭患者中，伴随着FGF 23增加和高磷酸盐血症，因此这种训练将在对严重的、常见的、无法治愈的疾病提供潜在重要影响的环境中进行。我们的初步结果强烈支持缺氧诱导因子（HIF）转录因子家族和FGF 23表达之间的新的相互作用。我们提出了铁和磷酸盐代谢之间的机制联系，通过关键的细胞铁/缺氧感应反应，驱动FGF 23的表达。因此，该提案将测试中心假设：缺铁和组织缺氧通过HIF依赖性机制升高FGF 23，导致磷酸盐代谢和严重内分泌性骨病的致病性紊乱。在目的1中，将使用具有骨特异性缺失HIF 1a和HIF抑制因子VHL的ADHR小鼠在铁缺乏和补充方案期间测试FGF 23表达的分子机制。将在Aim 2中使用检查FGF 23启动子突变和HIF 1a直接作用的体外方法检测控制FGF 23表达的转录机制。使用这些系统，Clinkenbeard博士将获得代谢性骨病转化模型的技能，这些模型在逻辑上建立在她之前的研究经验的基础上。这两个目标将共同提供优秀的研究培训，并有助于理解导致矿物质代谢内分泌紊乱的疾病机制。