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

基本信息

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
项目类别：
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

项目摘要

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：这项 NRSA 提案专为 Solis 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以他的未来目标为中心。记录、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 IUSM 和印第安纳肌肉骨骼健康中心 (ICMH) 将为成功完成做出贡献此外，还参与了“为未来教师和专业人员做好道德准备”计划。和资助写作课程、手稿准备、部门研讨会和期刊俱乐部以及国家会议将促进索利斯先生的职业发展，使其成为一名全面、独立的人申办者实验室和其他人之前的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 (FGF23) 突变导致严重的代谢性骨病， FGF23作为磷酸盐代谢的核心激素，是常见疾病的重要因素。改变磷酸盐处理，例如慢性肾病-矿物质和骨病（CKD-MBD），尽管在理解方面已取得进展，但循环浓度与患者死亡率相关。 CKD 磷酸盐处理的基本和临床方面，FGF23 的调控机制重要的是，CKD 中会出现组织慢性炎症。众所周知，特定细胞因子通过信号传导。 NF-κB 介导的机制，但该途径如何影响 FGF23 的作用实际上尚不清楚。肾脏炎症和 FGF23 升高与 CKD 的不良预后相关，因此确定 FGF23生物活性和促炎细胞因子相互关联的调控机制可以提供靶点我们的初步结果强烈支持这些途径之间的新相互作用。因此，我的中心假设是：NF-κB 活性负向调节肾脏 FGF23 介导的活性。矿物质代谢和 TNFα 驱动的炎症反应加剧了 CKD 中的这种效应。 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 TNF；细胞因子对 FGF23 过表达新模型和 CKD 中 FGF23 依赖性矿物质代谢的影响使用这些系统，Solis 先生将获得基因靶向方面的新研究技能。总的来说，该提案将利用最先进的翻译小鼠模型。为索利斯先生提供研究、伦理、书面和口头演讲培训，以及测试重要的疾病导致矿物质代谢内分泌紊乱的机制。