Targeting Inflammation to Improve FGF23-mediated Mineral Metabolism in CKD

项目摘要/摘要：这份为Solis先生量身定做的NRSA提案提供了高质量的博士后 研究、培训和职业发展都围绕着他未来的目标。赞助商的优秀指导 记录，与领先的骨骼和肾脏生物医学研究人员的合作，以及卓越的环境 在IUSM和印第安纳州肌肉骨骼健康中心(ICMH)的工作将有助于成功完成 这个项目的。此外，参与未来教师和专业人员的道德准备方案 并资助写作课程、手稿准备、部门研讨会和期刊俱乐部，以及国家 会议将加强Solis先生的职业发展，使他成为一个全面、独立的人 调查员。赞助者的实验室和其他实验室之前的研究已经确定了功能的获得和丧失 导致严重代谢性骨病的成纤维细胞生长因子-23(FGF23)突变， FGF23作为一种对磷酸盐代谢起中心作用的激素。FGF23是常见疾病中的一个重要因素。 改变的磷酸盐处理，如慢性肾脏疾病-矿物质和骨骼疾病(CKD-MBD)，具有高 循环浓度与患者死亡率相关。尽管在理解方面取得了进展 慢性肾脏病磷酸盐处理的基本和临床方面，调控FGF23的调节机制- 依赖的磷酸盐动态平衡仍然不清楚。重要的是，慢性肾脏病患者伴有组织炎症。 损伤并增加炎性细胞因子的产生。已知特定的细胞因子通过 然而，这一途径如何影响κ的作用尚不清楚。事实上，两者都是 肾脏炎症和FGF23升高与慢性肾脏病预后不良相关，因此确定 FGF23生物活性和促炎细胞因子相互作用的调节机制可以提供靶点 进行治疗干预。我们的初步结果有力地支持了这些通路和 FGF23生物活性。因此，我的中心假设是：NF-κB活性负向调节肾脏FGF23介导的 矿物质代谢和肿瘤坏死因子α驱动的炎症反应在慢性肾脏病中加剧了这种影响。在目标1中， 指示NF-κB调节FGF23生物活性的机制将在体外进行测试；Aim 2将测试肿瘤坏死因子 细胞因子对FGF23过度表达和CKD伴FGF23依赖的矿物质代谢的影响 基因消融的肿瘤坏死因子信号。使用这些系统，索利斯先生将在基因靶向方面获得新的研究技能 并利用最先进的平移鼠标模型。总体而言，这项建议将提供极好的 对Solis先生进行研究、伦理和书面和口头演示培训，以及测试重要疾病 导致矿物质代谢内分泌紊乱的机制。

Project Summary/Abstract: This NRSA proposal, tailored to Mr. Solis, provides high-quality predoctoral research training and career development centered upon his 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 Mr. Solis’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, the regulatory mechanisms governing FGF23- dependent phosphate homeostasis remain unclear. Importantly, chronic inflammation arises in CKD with tissue damage and increased production of inflammatory cytokines. It is known that specific cytokines signal through NF-κB-mediated mechanisms, however how this pathway influences FGF23 actions is unknown. Indeed, both renal inflammation and elevated FGF23 are associated with poor outcomes in CKD, therefore identifying regulatory mechanisms interconnecting FGF23 bioactivity and pro-inflammatory cytokines could provide targets for therapeutic intervention. Our initial results strongly support novel interactions between these pathways and FGF23 bioactivity. Thus, my central hypothesis is: NF-κB activity negatively regulates kidney FGF23-mediated mineral metabolism, and TNFα driven inflammatory responses exacerbate this effect in CKD. In Aim 1, the mechanisms dictating NF-κB regulation of FGF23 bioactivity will be tested in vitro; and Aim 2 will test TNF cytokines on FGF23-dependent mineral metabolism in novel models of FGF23 overexpression and in CKD with genetically ablated TNF signaling. Using these systems, Mr. Solis will gain new research skills in gene targeting and utilizing state of the art translational mouse models. Collectively, this proposal will provide excellent research, ethics, and written and oral presentation training to Mr. Solis, as well as test important disease mechanisms that result in endocrine disturbances of mineral metabolism.