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：尿路结石病 (USD) 是男性和女性中第三大常见且痛苦的泌尿系统疾病。预防 USD 及其相关成本和发病率需要了解早期和晚期 USD 新的证据表明肾内晶体成核、生长和肾内晶体之间的相互作用。吞噬细胞反应在 USD 中发挥着关键但未被认识的作用。磷酸钙 (CaP) 和草酸钙 (CaOx) 晶体诱导肾小管和吞噬细胞细胞因子、趋化因子和细胞外囊泡（EV；外泌体和微泡）的分泌。生物标志物可以吸引血液或驻留单核细胞并将单核细胞转化为亲（M1）或抗（M2）- 实验动物模型和人体组织中的观察表明炎症巨噬细胞（Mφ）。肾组织单核细胞和 Mφ 可以吞噬和代谢晶体和尿路结石形成物在高草酸尿小鼠模型中，髓质 M1 数量增加，M2 Mφ 数量减少。抑制单核细胞向 M2 Mφ 的转化显着增加了肾内 CaOx 沉积。还表明，携带来自特定节段的炎症标记物的 EV 经尿液排泄与对照组相比，特发性钙结石形成者（ICSF）的肾小管显着降低。因此，多种证据表明肾小管和单核细胞衍生的 Mφ 群体可以吞噬并作为晶体间隙机制降解晶体，这些间隙机制中的缺陷可能会导致间质兰德尔斑块（RP）和集合管塞（CDP），甚至直接生长成美元。拟议的研究项目旨在使用一种新颖的方法来评估 Mφ 在 RP 和 CDP 形成中的作用高钙尿症claudin-2全基因敲除小鼠模型（年龄超过3-24个月），类似于表型患有特发性高钙尿症和 USD 的患者（目标 1），并确定以下情况的频率和空间分布：使用羟基磷灰石、透钙磷石和仔细表型 ICSF（20-70 岁）中的单核细胞/ Mφ 群体草酸钙结石和不同数量的 RP（目标 2）。肾髓质促炎和抗炎吞噬细胞在 RP、CDP 和 USD 发展中的作用以及尿细胞因子、趋化因子或 EV 是否携带促/抗炎吞噬细胞生物标志物细胞可用于非侵入性监测肾内晶体沉积，这项研究的完成也将实现。促进组建一支技术精湛的多学科团队，其中包括一位有前途的早期外科医生科学家（Dr. Kevin Koo）在经验丰富且技术精湛的美国临床和研究人员（Lieske 博士）的指导下。由此产生的初步数据将提供我们团队有效性的证据。提交未来详细的拨款或中心提案，以扩展这些机制研究，并已阐明 USD 起源中潜在的致病步骤并确定新的治疗靶点具有巨大的潜力。