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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）：这项为 Clinkenbeard 博士量身定制的为期三年的 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。赞助商出色的指导记录、与领先的骨和肾脏生物医学研究人员的合作以及良好的环境将有助于该项目的成功完成。此外，参与“为未来教师做好准备”计划道德和资助写作课程、部门研讨会和期刊俱乐部以及全国会议将促进 Clinkenbeard 博士的职业发展，使其成为一名全面发展的独立研究者。申办者实验室和其他实验室之前的研究已经发现，成纤维细胞生长因子 23 (FGF23)（一种磷酸盐代谢的核心激素）的功能获得和丧失突变会导致严重的代谢性骨疾病。 FGF23 也正在成为磷酸盐处理改变的常见疾病（如 CKD-MBD）的重要因素，与患者死亡率、骨化醇治疗反应和心脏肥大相关。表达从常染色体显性低磷血症佝偻病 (ADHR) 患者中鉴定出的 FGF23 稳定突变 (R176Q) 的敲入小鼠被创建，以测试有关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 FGF23 而出现低磷血症，类似于 ADHR 患者的缺铁状态。重要的是，超过 70% 的终末期肾衰竭患者存在贫血，并伴有 FGF23 升高和高磷血症，因此本次培训将在对无法治愈的严重常见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 FGF23 表达之间的新相互作用。我们提出，通过驱动 FGF23 表达的关键细胞铁/缺氧传感反应，铁和磷酸盐代谢之间存在机制联系。因此，该提案将检验中心假设：缺铁和组织缺氧通过 HIF 依赖性机制升高 FGF23，导致磷酸盐代谢的致病性紊乱和严重的内分泌骨疾病。在目标 1 中，将使用骨特异性缺失 HIF1a 和 HIF 抑制因子 VHL 的 ADHR 小鼠，在缺铁和补充方案期间测试 FGF23 表达的分子机制。控制 FGF23 表达的转录机制将在目标 2 中使用体外方法进行测试，该方法检查 FGF23 启动子突变和 HIF1a 的直接作用。使用这些系统，Clinkenbeard 博士将获得代谢性骨疾病转化模型的技能，这些技能逻辑上建立在她之前的研究经验的基础上。这两个目标共同将提供出色的研究培训，并有助于了解导致矿物质代谢内分泌紊乱的疾病机制。