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

• 批准号: 10595343
• 负责人: John C Lieske
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/10595343
• 关键词: Address; Affect; Age-Months; Animal Model; Animals; 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; 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; 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; 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; cost; cytokine; design; exosome; experience; experimental study; extracellular vesicles; follow-up; human tissue; hypercalciuria; improved; inflammatory marker; innovation; insight; interstitial; macrophage; men; microvesicles; monocyte; mouse model; multidisciplinary; new therapeutic target; non-invasive monitor; novel; personalized management; prevent; programs; response; societal costs; therapeutic target; tool; translational scientist; translational study; ultrasound; urinary

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： 尿石病（USD）是男性和女性中第三大常见和痛苦的泌尿科疾病。 预防美元及其相关成本和发病率需要了解早期和晚期美元 发病。新兴的证据表明内部晶体成核，生长和 吞噬细胞细胞反应在美元中起关键但无法识别的作用。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 细胞因子，趋化因子和细胞外蔬菜（EV；外泌体和微囊泡）的分泌。这些 生物标志物可以吸引血液或居民单核细胞，并将单核细胞转化为Pro（M1）或抗（M2） - 炎症巨噬细胞（Mφ）。实验动物模型和人体组织中的观察表明 那个肾组织单核细胞和Mφ可以吞噬晶体并代谢晶体，以及尿石形成器 似乎增加了髓质M1并减少M2Mφ种群。在高氧化小鼠模型中 单核细胞对M2Mφ转化率的抑制显着增加了肾内CAOX沉积。我们的研究 还表明，具有特定段的炎症标记的电动汽车的尿排泄 与对照组相比，特发钙石材（ICSF）的肾脏块茎的肾块茎明显降低。 这是多种证据表明，结核病和单核细胞衍生的Mφ种群可以吞噬细胞。 和降解晶体作为晶体清除机制，以及这些清除机制中的缺陷 导致间质Randall的牌匾（RP）和收集管道插头（CDP），甚至直接成长为美元。 拟议的研究项目旨在评估Mφ在RP和CDP形成中的作用 高电钙Claudin-2全局敲除小鼠模型（超过3-24个月的年龄），类似于表型 特发性高钙尿和美元的患者（AIM 1），并定义 用羟基磷灰石，刷子和 草酸钙结石和不同量的RP（AIM 2）。拟议的创新研究将阐明 肾脏髓质和抗炎吞噬细胞在RP，CDP和USD发展中的作用 以及携带抗/抗炎吞噬性生物标志物的尿细胞因子，趋化因子或电动汽车 细胞可用于非侵入性监测内部晶体沉积。这项研究的完成也将 促进一个熟练的多学科团队的组成 凯文·库（Kevin Koo）在经验丰富且熟练的USD临床和研究人员（Lieske博士）的心态下。这 最终的初步数据将提供我们团队有效性的证据。这项工作也将启用 提交未来的详细赠款或中心建议，这些建议将扩展这些机械研究，并具有 在USD Genesis中阐明潜在的致​​病步骤并确定新型治疗靶标的巨大潜力。