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

• 批准号: 10170263
• 负责人: Dianne B Mckay
• 金额: $ 22.19万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170263
• 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; 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; therapeutically effective; tissue injury; transplant model

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：该提案研究了关键的细胞质先天免疫受体（即 模式识别受体 AIM2，调节 NLRP3 炎症小体的激活，从而防止 肾小管上皮细胞（RTE）损伤。该项目对于发生急性肾损伤非常重要 频繁并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 AIM2 在缺血再灌注损伤的情况下调节肾脏的损伤反应。 目标 1 询问 AIM2 如何在 RTE 中调节 NLRP3 炎性体（一种众所周知的肾 IR 损伤触发因素） 细胞（最容易受到肾 IR 损伤的细胞类型），通过定义 AIM2 调节机制 NLRP3炎症小体启动、组装；随后释放 IL1b/IL18 和细胞焦亡。 目标 2 侧重于了解 AIM2 在体内肾脏中的相对作用。旨在实现这一目标的实验将 使用肾脏广泛评估肾脏特异性损伤介质与炎症损伤介质 移植模型，允许在 WT 宿主和 WT 肾脏中研究 aim2-/- 肾脏的损伤反应 需要在aiim2-/-宿主中研究损伤。 项目的健康相关性：如果该提案的目标得以实现，我们将了解 AIM2 如何作为 肾脏损伤反应的负调节因子。这些知识对于理性的发展至关重要 在缺氧的临床情况下预防或改善肾损伤的靶向治疗 预计。关注缺血性肾损伤的最早事件最有希望有效治疗 治疗策略。