Targeting sKlotho-FGF23 Interactions to Improve Pathological Phosphate Handling in CKD

靶向 sKlotho-FGF23 相互作用以改善 CKD 中的病理磷酸盐处理

• 批准号: 10553159
• 负责人: KENNETH E WHITE
• 金额: $ 44.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553159
• 关键词: Acceleration; Acute; Affect; Alleles; Binding Proteins; Biochemical; Biological Process; Biology; Breeding; CRISPR/Cas technology; Cell surface; Cells; Cellular Membrane; Chronic; Chronic Kidney Failure; Clinical; Complex; Data; Data Set; Defect; Disease; Dissection; Etiology; Event; Exhibits; Experimental Genetics; FGFR1 gene; Familial hypophosphatemic bone disease; Familial tumoral calcinosis; Fibroblast Growth Factor Receptors; Fracture; Functional disorder; Genes; Genetic; Genetic Crosses; Genetic Models; Homeostasis; Hormones; Human; Hypophosphatemia; Impairment; In Vitro; Individual; Injections; Kidney; Kidney Diseases; Knockout Mice; Lead; Longevity; LoxP-flanked allele; MAP Kinase Gene; Mediating; Membrane; Metabolism; Minerals; Modeling; Molecular; Mus; Mutation; Nephrons; Onset of illness; Organ; Osteomalacia; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Physiological; Plasma; Play; Prevention; Production; Protein Isoforms; Proximal Kidney Tubules; Regulation; Renal Mass; Reporting; Resistance; Resolution; Rickets; Role; Secondary to; Serum; Severities; Signal Transduction; Site; Structure; Syndrome; Techniques; Testing; Time; Tissues; Validation; Vascular calcification; autosome; beta-site APP cleaving enzyme 1; cell type; design; dietary; extracellular; fibroblast growth factor 23; functional loss; improved; in vivo; in vivo Model; inorganic phosphate; insight; loss of function mutation; mortality; new therapeutic target; novel; novel therapeutics; nuclear factors of activated T-cells; positional cloning; prevent; rare mendelian disorder; receptor; response; sequencing platform; single-cell RNA sequencing; tissue injury; wasting

Project Summary/Abstract: Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis. We identified Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene responsible for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia, and fracture. The FGF23 co-receptor alpha-Klotho (KL), acting in a heteromeric complex with a canonical FGF receptor (FGFR), is required for normal phosphate metabolism. This is emphasized by the fact that KL loss of function mutations lead to end-organ FGF23 resistance, and cause the phenotypic reciprocal disorder to ADHR, hyperphosphatemic familial tumoral calcinosis (hfTC). In a similar manner, patients with chronic kidney disease (CKD) demonstrate impaired FGF23-responsiveness due to a loss of functional kidney mass and reduced Klotho expression, leading to increased serum phosphate concentrations and further increases in FGF23 production. KL is expressed as a membrane-bound protein (`mKL') that mediates FGF23-dependent signaling in target tissues, as well as a major circulating species that originates from the proteolytic cleavage of mKL within its juxta-extracellular membrane domain to derive a soluble form or `sKL'. Although the recent solving of the FGF23-sKL-FGFR1 triple crystal structure revealed insight into static sKL-FGF23 interactions, the complete scope of mKL versus sKL biological functions in the control of FGF23 and mineral metabolism remains unclear due to a lack of appropriate in vivo models. Our initial studies in mice with genetically reduced sKL expression showed aberrant FGF23 production in response to dietary phosphate challenges. Unlike global KL-KO mice, this model has the advantage of a lifespan that allows extended studies, providing new opportunities to gain critical insight into the regulation of FGF23 bioactivity in chronic conditions. Collectively, our results support mechanistic aims to identify specific sKL-FGF23 interactions in the control of phosphate metabolism, as well as to test sKL as a translational target in the treatment of human disorders. The central hypothesis to be tested in this proposal is: the sKL form of Klotho is required for normal FGF23-mediated phosphate handling and is protective during renal disease. We expect our studies using dovetailed, cutting-edge in vivo and in vitro techniques to provide novel, translational insight into the basic biology of phosphate metabolism, as well as into both rare and common syndromes of altered Klotho and FGF23 expression.

项目摘要/摘要：探讨矿物质干扰所致疾病的分子病因