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

• 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
• 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

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)：这项为期三年的NRSA培训计划是为克林肯胡德博士量身定做的，以她未来的目标为中心，提供高质量的研究、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出色的环境将有助于该项目的成功完成。此外，参与准备未来的教员计划 伦理和拨款撰写课程、部门研讨会和期刊俱乐部以及国家会议将促进克林肯胡德博士的职业发展，使其成为一名全面、独立的研究员。赞助商实验室和其他实验室之前的研究已经确定，成纤维细胞生长因子-23(FGF23)功能突变的得失会导致严重的代谢性骨骼疾病。成纤维细胞生长因子-23是一种对磷酸盐代谢至关重要的激素。此外，FGF23也是CKD-MBD等常见疾病中的一个重要因素，与患者死亡率、对降钙素治疗的反应和心肌肥厚有关。从常染色体显性遗传性低磷血症(ADHR)患者中发现了一种表达FGF23稳定突变(R176Q)的敲入小鼠，以检验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%的终末期肾功能衰竭患者会出现贫血，并伴有FGF23升高和高磷血症，因此，这项训练将在对一种无法治愈的严重、常见疾病提供潜在重要影响的环境中进行。我们的初步结果有力地支持了缺氧诱导因子(HIF)转录因子家族和FGF23表达之间的新的相互作用。我们提出了铁和磷代谢之间的机制联系，通过关键的细胞铁/低氧感应反应来驱动FGF23的表达。因此，这一提议将检验中心假说：缺铁和组织缺氧通过HIF依赖的机制上调FGF23，导致磷酸盐代谢的病理性紊乱和严重的内分泌性骨病。在目标1中，将使用骨特异性缺失HIF1a的ADHR小鼠和HIF抑制因子VHL，在缺铁和补充铁的方案中测试FGF23表达的分子机制。控制FGF23表达的转录机制将在AIM 2中使用体外方法测试FGF23启动子突变和HIF1a的直接作用。使用这些系统，克林肯比尔德博士将在代谢性骨骼疾病的翻译模型方面获得技能，这些模型在逻辑上建立在她之前的研究经验的基础上。这两个目标结合在一起，将提供极好的研究培训，并有助于了解导致矿物质代谢内分泌紊乱的疾病机制。