Targeting Inflammation to Improve FGF23-mediated Mineral Metabolism in CKD

靶向炎症以改善 CKD 中 FGF23 介导的矿物质代谢

• 批准号: 10750425
• 负责人: Emmanuel Solis
• 金额: $ 3.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750425
• 关键词: ATAC-seq; Ablation; Adenine; Affect; Automobile Driving; Binding; Biochemistry; Bone Diseases; Cells; Chronic; Chronic Kidney Failure; Clinical; Collaborations; Complex; Cytokine Signaling; Disease; Disease Progression; Educational Status; Endocrine; Endocrine System Diseases; Environment; Ethics; Family member; Fibroblast Growth Factor Receptors; Functional disorder; Future; Future Teacher; Gene Expression; Gene Family; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Grant; Health; Homeostasis; Hormones; I-kappa B Proteins; Immunoblot Analysis; In Vitro; Indiana; Inflammation; Inflammatory; Inflammatory Response; Journals; Kidney; Lead; Lipopolysaccharides; LoxP-flanked allele; MAP Kinase Gene; Manuscripts; Mediating; Mentors; Messenger RNA; Metabolic Bone Diseases; Metabolism; Minerals; Modeling; Molecular; Mus; Musculoskeletal; NF-kappa B; National Research Service Awards; Oral; Organ; Osteocytes; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Plasma; Preparation; Production; Progressive Disease; Protein Isoforms; Proximal Kidney Tubules; Recombinants; Regulation; Regulatory Pathway; Renal function; Repression; Research; Research Personnel; Research Training; Resistance; Secondary Hyperparathyroidism; Signal Transduction; Stimulus; System; TLR4 gene; TNF gene; Testing; Therapeutic Intervention; Tissues; Training; Transfection; Transgenic Mice; Vitamin D; Western Blotting; Writing; absorption; bone; career development; cytokine; fibroblast growth factor 23; gain of function; improved; improved outcome; in vitro testing; in vivo; inflammatory marker; inorganic phosphate; loss of function; loss of function mutation; meetings; mortality; mouse model; multiple omics; new therapeutic target; novel; overexpression; pre-doctoral; programs; rare mendelian disorder; receptor; response; single-cell RNA sequencing; skeletal; skeletal disorder; skills; targeted treatment; transcriptome sequencing

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.

项目概要/摘要：这个NRSA提案，为索利斯先生量身定制，提供高质量的博士前课程。 研究培训和职业发展集中在他的未来目标。赞助商的优秀指导 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 在IUSM和印第安纳州肌肉骨骼健康中心（ICMH）的研究将有助于成功完成 of this project项目.此外，参加准备未来的教师和专业人员的道德方案， 和赠款写作课程，手稿准备，部门研讨会和期刊俱乐部，以及国家 会议将加强索利斯先生的职业发展，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功能的获得和丧失 成纤维细胞生长因子-23（FGF 23）突变导致严重的代谢性骨病， FGF 23作为磷酸盐代谢的核心激素。FGF 23是一个重要的因素，在常见的疾病， 磷酸盐处理改变，如慢性肾脏疾病-矿物质和骨疾病（CKD-MBD）， 与患者死亡率相关的循环浓度。尽管在理解方面取得了进展， CKD中磷酸盐处理的基础和临床方面，控制FGF 23- 依赖磷酸盐的体内平衡仍不清楚。重要的是，慢性炎症在CKD中出现， 损伤和炎性细胞因子的产生增加。已知特异性细胞因子通过 NF-κ B介导的机制，然而该途径如何影响FGF 23的作用尚不清楚。事实上，两者 肾脏炎症和FGF 23升高与CKD的不良结局相关，因此， 将FGF 23生物活性和促炎细胞因子相互联系的调节机制可以提供靶点， 进行治疗干预。我们的初步结果强烈支持这些途径之间的新型相互作用， FGF 23生物活性。因此，我的中心假设是：NF-κB活性负调节肾脏FGF 23介导的 矿物质代谢和TNFα驱动的炎症反应加剧了CKD中的这种作用。在目标1中， 将在体外测试NF-κB调节FGF 23生物活性的机制; Aim 2将测试TNF 在FGF 23过表达的新模型和CKD中细胞因子对FGF 23依赖性矿物质代谢的影响 基因消融TNF信号传导。利用这些系统，索利斯先生将获得新的基因靶向研究技能 并利用现有技术水平的翻译小鼠模型。总的来说，这项提案将提供出色的 研究，道德，书面和口头介绍培训索利斯先生，以及测试重要的疾病 导致矿物质代谢的内分泌紊乱的机制。