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Renal macrophages in the pathogenesis of human urinary stones and Randall's plaque formation in mice

肾巨噬细胞在人类尿结石发病机制和小鼠兰德尔斑块形成中的作用

基本信息

批准号：
10708970
负责人：
John C Lieske
金额：
$ 39.41万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708970
关键词：
Address Affect Age Months Animal Experiments Animal Model Anti-Inflammatory Agents Applications Grants Automobile Driving Biological Markers Blood Breeding Calcium Calcium Oxalate Cell secretion Cells Clinic Clinical Clinical Investigator Clinical Treatment Communities Complement County Crystal Formation Crystallization Data Dedications Defect Deposition Development Disease Disease Management Duct (organ) structure Economic Models Education Effectiveness Event Excretory function Experimental Animal Model Fostering Frequencies Future Genitourinary system Goals Grant Growth Hematology Human Hydroxyapatites In Vitro Incidence Infection Inflammatory Interdisciplinary Study Investigation Kidney Kidney Calculi Knockout Mice Knowledge Lesion Life Macrophage Medical Care Costs Mentorship Modeling Molecular Morbidity - disease rate Mus National Institute of Diabetes and Digestive and Kidney Diseases Nephrology Pain Pathogenesis Pathogenicity Patients Persons Phagocytes Phenotype Physiology Play Population Positioning Attribute Predisposition Prevalence Prevention Prevention strategy Productivity Recurrence Renal Tissue Renal tubule structure Reporting Research Research Personnel Research Project Grants Risk Risk Factors Role Scientist Seasons Spatial Distribution Surgeon Tubular formation United States Urinary Calculi Urine Urologic Diseases Urology Woman Work brushite calcification calcium excretion calcium phosphate chemokine clinical investigation comparison control cost cytokine design exosome experience experimental study extracellular vesicles follow-up human tissue hypercalciuria improved inflammatory marker innovation insight interstitial men microvesicles monocyte mouse model multidisciplinary new therapeutic target non-invasive monitor novel personalized management prevent programs response skills societal costs synergism therapeutic target tool translational scientist translational study ultrasound urinary

项目摘要

Project Summary/Abstract: Urinary stone disease (USD) is third most common and painful urological disease in men and women. Prevention of USD and its associated costs and morbidity requires an understanding of early and late USD pathogenesis. Emerging evidence suggests interactions between intrarenal crystal nucleation, growth, and phagocytic cellular responses plays a key but unrecognized role in USD. Studies in vitro demonstrate that calcium phosphate (CaP) and calcium oxalate (CaOx) crystals induce renal tubular and phagocytic cell secretion of cytokines, chemokines, and extracellular vesicles (EVs; exosomes and microvesicles). These biomarkers can attract blood or residential monocytes and convert monocytes into pro (M1) or anti (M2)- inflammatory macrophages (Mφ’s). Observations in experimental animal models and human tissues suggests that renal tissue monocytes and Mφ’s can phagocytose and metabolize crystals, and urinary stone formers appear to have increased medullary M1 and decreased M2 Mφ populations. In a hyperoxaluric mouse model, suppression of monocyte to M2 Mφ conversion significantly increased intrarenal CaOx deposition. Our studies also demonstrated that urinary excretion of EVs bearing inflammatory markers derived from specific segments of renal tubules were significantly lower in idiopathic calcium stone formers (ICSFs) compared to controls. Thus, multiple lines of evidence suggest that tubular and monocyte derived Mφ populations can phagocytose and degrade crystals as a crystal clearance mechanism, and defects in these clearance mechanisms could result in interstitial Randall’s plaque (RP) and collecting duct plugs (CDP) or even grow directly into USD. The proposed research project is designed to evaluate the role of Mφ’s in RP and CDP formation using a novel hypercalciuric claudin-2 global knockout mouse model (over 3-24 months age) that resembles the phenotype of patients with idiopathic hypercalciuria and USD (Aim 1), and to define the frequency and spatial distribution of monocyte/ Mφ populations in carefully phenotyped ICSFs (20-70 years) with hydroxyapatite, brushite, and calcium oxalate stones and varying amounts of RP (Aim 2). The proposed innovative study will elucidate the role of renal medullary pro-and anti-inflammatory phagocytic cells in the development of RP, CDP, and USD and whether urinary cytokines, chemokines or EVs carrying biomarkers of pro-/anti-inflammatory phagocytic cells can be used to non-invasively monitor intrarenal crystal deposition. Completion of this study will also facilitate the formation of a skilled multidisciplinary team including a promising early-stage surgeon-scientist (Dr Kevin Koo) under the mentorship of an experienced and skilled USD clinical and researcher (Dr. Lieske). The resulting preliminary data will provide evidence of the effectiveness of our team. This work will also enable submission of future detailed grant or center proposals that will extend these mechanistic studies, and has great potential to elucidate underlying pathogenic steps in USD genesis and identify novel therapeutic targets.

项目总结/文摘: