New strategies to study malaria-induced acute kidney injury

研究疟疾引起的急性肾损伤的新策略

• 批准号: 10681439
• 负责人: Julio Gallego-Delgado
• 金额: $ 15.72万
• 依托单位: HERBERT H. LEHMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681439
• 关键词: Acute Kidney Tubular Necrosis; Acute Renal Failure with Renal Papillary Necrosis; Adult; Apoptosis; Apoptotic; Architecture; Award; Basic Science; Biological Markers; Biological Models; Blood; Blood Urea Nitrogen; Blood Vessels; CASP3 gene; Case Fatality Rates; Cell Death; Cells; Cessation of life; Child; Coculture Techniques; Communities; Complication; Creatinine; Cytolysis; Data; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Early identification; Endothelium; Epithelium; Erythrocytes; Experimental Models; Foundations; Generations; Glomerular Filtration Rate; Glomerulonephritis; Goals; Harvest; Health; Heme; Hemoglobin; Home; Hospitals; Human; Immune; Immunofluorescence Immunologic; Impairment; In Vitro; Incubated; Infection; Injury; Injury to Kidney; Innovative Therapy; Interstitial Nephritis; Kidney; Kinetics; Knowledge; Laboratories; Life Cycle Stages; Malaria; Measures; Mediating; Metabolic; Mission; Modeling; Molecular; Mus; Necrosis; Nephrectomy; Oliguria; Operative Surgical Procedures; Output; Oxidative Stress; Oxidative Stress Induction; Parasites; Pathology; Pathway interactions; Patients; Physiological; Pilot Projects; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Proliferating; Proteome; Public Health; Publishing; Renal Tissue; Renal function; Reporting; Research; Research Project Grants; Rupture; Serum; Signal Pathway; Testing; Tissues; Tubular formation; United States National Institutes of Health; Uric Acid; Urine; Vertebrates; Western Blotting; Wild Type Mouse; accurate diagnosis; cytotoxic; cytotoxicity; effective therapy; hemodynamics; improved; in vitro Assay; in vitro Model; in vivo; in vivo Model; innovation; kidney cell; malaria infection; mortality; mouse model; neglect; new technology; novel; novel therapeutics; organ on a chip; parasite invasion; pediatric patients; physiologic model; tool

PROJECT SUMMARY Malaria-induced acute kidney injury (MAKI) is one of the most severe complications of malaria and the strongest indicator of death in both adults and children. The impact of this specific complication has been largely under-recognized, and its study neglected. There is a lack of suitable model systems for elucidating the mechanisms that lead to renal impairment during malaria infection. The current gap in knowledge is impeding ef- forts to develop accurate diagnoses and effective therapies to treat MAKI. There is, therefore, a critical need to develop experimental models to study the molecular mechanisms of MAKI. The long-term goal of this study is to develop new therapies for MAKI and identify early and accurate biomarkers of MAKI, to better diagnose and treat this disease. The overall objectives in this application are to (i) establish the scientific framework needed to study MAKI in vitro and in vivo and (ii) determine the molecular mechanism(s) by which malaria parasites induce acute kidney injury. The central hypothesis is that rupture of P. falciparum-infected red blood cells (Pf- iRBCs) releases components that directly promote acute tubular necrosis (ATN)—the hallmark of MAKI. The rationale that underlies the proposed research is that establishing the foundation for MAKI basic research and unveiling the molecular mechanisms that promote renal impairment in malaria will facilitate progress towards more sensitive diagnoses and effective treatments for MAKI. The central hypothesis will be tested by pursuing two specific aims: 1) Develop a physiological mouse model of MAKI to identify the molecular pathways leading to ATN; and 2) Identify molecular mechanisms of MAKI using in vitro assays. Under the first aim, mice will un- dergo renal surgery before infection with Plasmodium-rodent spp. The renal function will be evaluated by measuring urine output, glomerular rate filtration, blood urea nitrogen, serum creatinine levels and expression of biomarkers of acute kidney injury. Kidney tissues will be harvested for analysis of cell death pathway activa- tion as well as levels of oxidative stress. For the second aim, primary human renal tubular and microvascular cells will be co-cultured using novel technology (Organ-on-a-chip) to mimic the natural architecture of the kid- ney. Cultures will be incubated with the contents released upon bursting of Pf-iRBCs to investigate the effect(s) on endothelial-epithelial barrier integrity, tubular cytotoxicity and activation of cell death pathways. The re- search proposed in this application is innovative, as it will provide the scientific community with new physiologi- cal models of MAKI. The models will not involve the use of high vertebrate animals, which makes them acces- sible for most laboratories, and unlike other attempted models, these models are specific for the human renal pathology associated with malaria. The proposed research is significant because it is expected to provide a strong scientific basis on which to advance the understanding of the signaling pathways involved in this pathol- ogy. The results of this study will contribute to the development of innovative therapies and diagnostic tests for MAKI, which will ultimately reduce malaria mortality in both adults and children.

项目摘要 疟疾引起的急性肾脏损伤（MAKI）是疟疾最严重的并发症之一， 成人和儿童死亡的最强指标。这种特定并发症的影响是 在很大程度上被识别得不足，其研究被忽略了。缺乏合适的模型系统来阐明 导致疟疾感染期间肾功能障碍的机制。当前的知识差距阻碍了EF- 开发准确的诊断和有效治疗Maki的疗法的堡垒。因此，迫切需要 开发实验模型来研究maki的分子机制。这项研究的长期目标是 为Maki开发新疗法并确定Maki的早期和准确的生物标志物，以更好地诊断和 治疗这种疾病。本应用程序中的总体目标是（i）建立所需的科学框架 在体外和体内研究maki，以及（ii）确定疟疾寄生虫的分子机制 诱发急性肾脏损伤。中心假设是恶性疟原虫感染的红细胞破裂（PF- IRBCS）释放直接促进急性管状坏死（ATN）的组件 - Maki的标志。这 拟议研究基础的基本原理是建立Maki基础研究基础 揭示促进疟疾肾脏损害的分子机制将有助于进步 更敏感的诊断和对Maki的有效治疗方法。中心假设将通过追求来检验 两个具体的目的：1）开发Maki的物理小鼠模型，以识别前进的分子途径 到ATN; 2）使用体外测定法确定MAKI的分子机制。在第一个目标下，小鼠会不 在感染疟原虫属的肾脏手术中。肾功能将通过 测量尿量输出，肾小球速率过滤，血液尿素氮，血清肌酐水平和表达 急性肾损伤的生物标志物。将收集儿童组织以分析细胞死亡途径Activa- 氧化应激水平以及水平。对于第二个目标，主要人类肾小管和微血管 细胞将使用新型技术（芯片上的器官）共同培养，以模仿孩子的自然结构 尼。培养物将与PF-IRBC破裂后释放的内容一起孵育，以研究效果 在内皮上皮屏障完整性上，管状细胞毒性和细胞死亡途径的激活。那里- 本应用程序中提出的搜索具有创新性，因为它将为科学界提供新的生理学 - Maki的Cal模型。这些模型将不涉及使用高脊椎动物的动物，这使它们进入 - 对于大多数实验室而言，与其他尝试的模型不同，这些模型特定于人类肾脏 与疟疾相关的病理学。拟议的研究很重要，因为它有望提供 强烈的科学基础，以提高对此病理中涉及的信号通路的理解的理解 OGY。这项研究的结果将有助于开发创新疗法和诊断测试 马基（Maki），最终将降低成人和儿童的疟疾死亡率。

项目成果

Pathology of Severe Malaria.

• DOI: 10.3390/pathogens12121389
• 发表时间: 2023-11-25
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Gallego-Delgado J

Novel Experimental Mouse Model to Study Malaria-Associated Acute Kidney Injury.

• DOI: 10.3390/pathogens12040545
• 发表时间: 2023-04-01
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Bensalel J;Roberts A;Hernandez K;Pina A;Prempeh W;Babalola BV;Cannata P;Lazaro A;Gallego-Delgado J
• 通讯作者: Gallego-Delgado J