权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要/摘要：尿石症是男性和女性的第三大常见和痛苦的泌尿系疾病。预防美元及其相关成本和发病率需要了解美元的早期和晚期发病机制。新的证据表明，肾内晶体成核、生长和吞噬细胞反应在慢性阻塞性肺疾病中起着关键但尚未被认识的作用。体外研究表明，磷酸钙(CaP)和草酸钙(CaOx)晶体诱导肾小管和吞噬细胞分泌细胞因子、趋化因子和细胞外小泡(EVS；外切体和微泡)。这些生物标志物可以吸引血液或居留单核细胞，并将单核细胞转化为亲(M1)或抗(M2)- 炎性巨噬细胞(Mφ‘S)。对实验动物模型和人体组织的观察表明肾组织单核细胞和Mφ的S能吞噬和代谢晶体，并形成尿结石似乎增加了延髓M1，减少了M2 Mφ数量。在高草酸尿小鼠模型中，抑制单核细胞向M2 Mφ转化显著增加肾内CaOx沉积。我们的研究还表明，携带炎症标志物的EV的尿液排泄来自特定节段特发性钙结石患者(ICSFs)的肾小管密度明显低于对照组。因此，多条证据表明，小管和单核细胞来源的M-φ群体可以吞噬并降解晶体作为晶体清除机制，这些清除机制中的缺陷可能导致间质性Randall‘s斑块(RP)和集合管堵塞(CDP)，甚至直接生长到UD。这个提出的研究项目旨在评估Mφ的S在RP和cdp形成中的作用。高钙尿型Claudin-2全球基因敲除小鼠模型(3-24个月以上)，类似于特发性高钙尿症患者和美元(目标1)，并确定频率和空间分布 ICSFs(20-70年)中的单核细胞/M-φ群体，包括羟基磷灰石、刷石和草酸钙结石和不同数量的RP(目标2)。拟议的创新研究将阐明肾髓质促炎症吞噬细胞和抗炎吞噬细胞在RP、CDP和US发生发展中的作用无论是尿液中的细胞因子、趋化因子还是携带促/抗炎吞噬细胞生物标志物的EV 细胞可用于非侵入性监测肾内晶体沉积。这项研究的完成还将促进形成一支技术娴熟的多学科团队，其中包括一名有前途的早期外科医生兼科学家(Dr Kevin Koo)在经验丰富、技术熟练的美国联合大学临床和研究员(Lieske博士)的指导下进行治疗。这个由此产生的初步数据将为我们团队的有效性提供证据。这项工作还将使提交未来详细的拨款或中心建议，以延长这些机械性研究，并已巨大的潜力，以阐明美元的发生和确定新的治疗靶点潜在的致病步骤。