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: 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
• 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

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：这项建议研究了一种关键的细胞质天然免疫受体，即 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。该项目对急性肾损伤具有非常重要的意义 经常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确定如何激活 AIM2对肾缺血再灌注损伤的损伤反应具有调节作用。 目的1问AIM2如何在RTE中调节NLRP3炎症小体(一种众所周知的肾IR损伤的触发因素) 细胞(最容易受到肾脏IR损伤的细胞类型)，通过定义AIM2调节机制 NLRP3炎性小体的启动、组装，以及随后IL1b/IL18的释放和下垂。 目的2了解AIM2在活体肾脏中的相对作用。这一目标的实验将 使用肾脏广泛评估损伤的肾脏特异性介质与损伤的炎性介质 移植模型，允许在WT宿主中研究AIM2/-肾的损伤反应，以及WT肾 损伤将在AIM2-/-宿主中进行研究。 项目的健康相关性：如果达到本提案的目标，我们将了解AIM2如何作为 肾脏损伤反应的负性调节因子。这一知识对于Rational的发展至关重要 在临床缺氧的情况下预防或改善肾损伤的靶向治疗 已经预料到了。关注缺血性肾损伤的早期事件是有效的最大希望 治疗策略。