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.

项目摘要/摘要：该NRSA提案为Solis先生量身定制，提供高质量的博士预科课程