Role of NLRP3 signals in ischemia/reperfusion-induced organ injury

NLRP3信号在缺血/再灌注引起的器官损伤中的作用

• 批准号: 10555070
• 负责人: Dianne B Mckay
• 金额: $ 92.44万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555070
• 关键词: 2019-nCoV; Acute; Acute Disease; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Animal Model; Area; Biochemical; Biological; COVID-19; COVID-19 patient; COVID-19 survivors; Cells; Chronic; Chronic Kidney Failure; Clinical; Complement; Data; Development; Disease; Disease Progression; Dose; Epithelial; Epithelial Cells; Event; Exhibits; Fibrosis; Gene Expression; Gene Expression Profile; Genes; Goals; Health; Histologic; Human; IL18 gene; Immune; Immune response; Immune signaling; Immunologic Receptors; In Vitro; Infection; Inflammasome; Inflammation Mediators; Inflammatory; Injury; Injury to Kidney; Ischemia; K-18 conjugate; Kidney; Knowledge; Laboratories; Learning; Link; Long COVID; Lung; Mediating; Middle East Respiratory Syndrome Coronavirus; Molecular; Morbidity - disease rate; Mouse Strains; Multiprotein Complexes; Mus; Natural Immunity; Organ; Organoids; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmacology; Play; Post-Acute Sequelae of SARS-CoV-2 Infection; Prevention therapy; Primary Infection; Proteins; Regulation; Renal tubule structure; Reperfusion Therapy; Reporting; Research; Research Design; Research Methodology; Role; SARS coronavirus; SARS-CoV-2 infection; Severities; Signal Pathway; Signal Transduction; Study models; Survivors; Symptoms; System; Testing; Time; Tissues; Tubular formation; United States; Viral; Virus Replication; cell type; cohort; coronavirus disease; experience; high risk; human model; in vivo; induced pluripotent stem cell; inhibitor; innate immune pathways; insight; kidney biopsy; kidney fibrosis; kidney infection; long term consequences of COVID-19; marenostrin; mortality; mouse model; novel therapeutics; organ injury; post SARS-CoV-2 infection; prevent; programs; response; sensor; severe COVID-19; targeted agent; targeted treatment; transcriptome sequencing

Project Summary: This proposal evaluates how the cytoplasmic innate immune receptor, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) contributes to chronic kidney disease (CKD) after SARS-CoV2 infection of human and murine kidneys. The project is highly significant for understanding the steps leading to chronic renal injury associated with COVID-19 disease. Broad/long-term objectives: The long-term goals of the proposed research are to define how activation of NLRP3 contributes to chronic injurious tissue responses in human kidneys following SARS-CoV2 infection. Specific Aims: The central goal of this proposal is to test the hypothesis that SARS-CoV2 infection triggers cell- type specific responses that affect the NLRP3 pathway, and that dysregulation of this pathway contributes to the pathogenesis of CKD as a post-acute sequalae of COVID-19 disease. Research Design and Methods for Achieving the Stated Goals: Aim 1 will examine the effect of SARS-CoV2 infection on NLRP3 pathway activation and its functional consequences in human and murine renal tubular epithelia and will test consequences of blockade. Aim 2 will examine how SARS-CoV2 infection induces chronic kidney injury using two murine models of infection, and tests whether blockade of NLRP3 signaling pathways prevents that injury. Aim 3 will examine the consequences of NLRP3 pathway activation and blockade in SARS-CoV2 chronically infected human kidney organoids. Health Relatedness of Project: If the aims of this proposal are met we will learn how activation of NLRP3 contributes to the pathogenesis of the post-acute sequalae of CKD after COVID-19 disease. This knowledge is crucial for the development of rational target therapies for prevention or amelioration of organ injury following SARS- CoV2 infection.

项目摘要：这项提案评估了细胞质天然免疫受体、NOD、LRR和吡喃 含结构域蛋白3(NLRP3)与SARS-CoV2感染后慢性肾脏病(CKD)的关系 人和小鼠的肾脏。该项目对于了解导致慢性肾脏疾病的步骤具有重要意义 与新冠肺炎病相关的伤害。 广泛/长期目标：拟议研究的长期目标是确定NLRP3如何激活 导致SARS-CoV2感染后人类肾脏的慢性损伤组织反应。 具体目标：这项提案的中心目标是测试SARS-CoV2感染触发细胞- 影响NLRP3途径的类型特异性反应，该途径的失调有助于 新冠肺炎病急性后遗症慢性肾脏病的发病机制。 研究设计和实现所述目标的方法：目标1将检查SARS-CoV2的影响 感染对人和小鼠肾小管上皮细胞NLRP3通路激活及其功能的影响 并将测试封锁的后果。目标2将研究SARS-CoV2感染如何导致慢性肾脏 使用两种小鼠感染模型，并测试阻断NLRP3信号通路是否可以阻止 受伤。AIM 3将长期检测SARS-CoV2中NLRP3通路的激活和阻断的后果 受感染的人类肾脏器官。 项目的健康相关性：如果达到本提案的目标，我们将了解NLRP3如何激活 参与新冠肺炎病后慢性肾脏病急性后遗症的发病机制。这一知识是 对于开发预防或改善SARS后器官损伤的合理靶向治疗至关重要- CoV2感染。