AIM2 as a negative regulator of renal ischemia/reperfusion injury

AIM2 作为肾缺血/再灌注损伤的负调节因子

基本信息

批准号：
10043487
负责人：
Dianne B Mckay
金额：
$ 26.63万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-22 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043487
关键词：
AIM2 gene Acute Renal Failure with Renal Papillary Necrosis Address Apoptosis Blood flow Caspase Cell Death Cells Cellular Stress Chronic Kidney Failure Clinical Complex DNA Data Development Elements Epithelial Cells Evaluation Event Functional disorder Genetic Genetic Transcription Goals Harvest Health Human Hypoxia IL18 gene Immunologic Receptors Inflammasome Inflammation Inflammation Mediators Inflammatory Injury Injury to Kidney Innate Immune System Institution Interferons Kidney Kidney Transplantation Knowledge Laboratories Learning Mediating Mediator of activation protein Molecular Target Mus Operative Surgical Procedures Oxidative Stress Pathogenicity Patients Pattern recognition receptor Play Prevention therapy Preventive Process Proteins Regulation Reperfusion Injury Research Rodent Model Role TLR2 gene Testing Therapeutic Transplantation Treatment Efficacy Tubular formation Up-Regulation Work animal facility biological adaptation to stress cell injury cell type clinical development clinically relevant cytokine experimental study human model in vivo injured man meetings novel pathogen prevent recruit renal hypoxia renal ischemia response response to injury targeted treatment tissue injury transplant model

项目摘要

Project Summary: This proposal studies how activation of a key cytoplasmic innate immune receptor, the pattern recognition receptor AIM2, regulates activation of the NLRP3 inflammasome and thus protects from renal tubular epithelial cell (RTE) injury. The project is highly significant for acute kidney injury, which occurs frequently and leads to the burden of chronic kidney disease. Broad/long-term objectives: The long-term goals of the proposed research are to define how activation of AIM2 regulates injury responses in the kidney in the setting of ischemia reperfusion injury. Aim 1 asks how AIM2 regulates the NLRP3 inflammasome (a well-described trigger of renal IR injury) in RTE cells (the cell type most vulnerable to renal IR injury), by defining the mechanisms by which AIM2 regulates NLRP3 inflammasome priming, assembly; and subsequent release of IL1b/IL18 and pyroptosis. Aim 2 focuses on understanding the relative role of AIM2 in the kidney in vivo. The experiments in this aim will broadly assess kidney-specific mediators of injury vs. inflammatory mediators of injury using a kidney transplant model that allows injury responses of the aim2-/- kidney to be studied in a WT host, and WT kidney injury to be studied in the aim2-/- host. Health Relatedness of Project: If the aims of this proposal are met we will learn how AIM2 participates as a negative regulator of injury responses in the kidney. This knowledge is crucial for the development of rational targeted therapies for prevention or amelioration of renal injury in clinical situations where hypoxia is anticipated. Focusing on the earliest events of ischemic kidney injury holds the greatest promise for effective therapeutic strategies.

项目摘要：该建议研究关键细胞质先天免疫受体的激活如何激活模式识别受体AIM2，调节NLRP3炎症体的激活，从而保护肾小管上皮细胞（RTE）损伤。该项目对于发生的急性肾脏损伤非常重要经常导致慢性肾脏疾病的负担。广泛/长期目标：拟议研究的长期目标是定义如何激活在缺血再灌注损伤的情况下，AIM2调节肾脏的损伤反应。 AIM 1询问AIM2如何调节RTE中的NLRP3炎症体（肾脏IR损伤的触发器）通过定义AIM2调节的机制，细胞（最容易受到肾脏IR损伤的细胞类型） NLRP3炎性体启动，组装；随后释放IL1B/IL18和凋亡。 AIM 2专注于了解AIM2在体内肾脏中的相对作用。这个目标的实验将广泛评估使用肾脏的肾脏损伤介质的肾脏特异性介质可以在WT宿主中研究AIM2 - / - 肾脏的损伤反应的移植模型，WT肾脏在AIM2 - / - 主机中进行的伤害。项目的健康相关性：如果满足该提案的目的，我们将了解AIM2如何参与肾脏受伤反应的负调节剂。这些知识对于发展理性至关重要在缺氧的临床情况下预防或改善肾脏损伤的靶向疗法预期。专注于缺血性肾脏损伤的最早事件是有效的最大希望治疗策略。