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

基本信息

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
项目类别：
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

项目摘要

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：该提案评估了细胞质先天免疫受体，点头，LRR-和pyrin如何 SARS-COV2感染后，含域的蛋白3（NLRP3）有助于慢性肾脏疾病（CKD）人和鼠肾。该项目对于理解导致慢性肾脏的步骤非常重要与Covid-19疾病有关的损伤。广泛/长期目标：拟议研究的长期目标是定义NLRP3的激活方式 SARS-COV2感染后，有助于人肾脏的慢性造成伤害组织反应。具体目的：该提案的核心目标是检验以下假设：SARS-COV2感染触发细胞 - 影响NLRP3途径的特定响应，该途径的失调有助于 CKD作为Covid-19疾病的急性后序列的发病机理。实现既定目标的研究设计和方法：AIM 1将检查SARS-COV2的效果 NLRP3途径激活的感染及其在人和鼠肾小管上皮中的功能后果并将测试封锁的后果。 AIM 2将检查SARS-COV2感染如何诱导慢性肾脏使用两种鼠类感染模型的伤害，并测试NLRP3信号通路的封锁是否阻止受伤。 AIM 3将检查NLRP3途径激活和封锁SARS-COV2的后果。被感染的人类肾脏器官。项目的健康相关性：如果满足该提案的目的，我们将学习如何激活NLRP3 有助于CKD疾病后CKD急性后序列的发病机理。这些知识是对于预防或改善器官损伤后的理性目标疗法的发展至关重要 COV2感染。