Role of Nlrp3 in Ischemic Organ Injury

描述(申请人提供)：这项研究考察了一种称为Nlrp3的细胞内模式识别受体如何在小鼠肾缺血再灌注(IR)损伤模型中对急性肾损伤起作用。实验性肾脏IR损伤类似于缺血性急性肾损伤，后者是住院患者发病率和死亡率的主要原因。广泛/长期目标：拟议研究的长期目标是确定Nlrp3如何促进肾脏的损伤组织反应。具体目的：这项建议的具体目的是验证细胞质PRR Nlrp3是肾脏IR损伤发病机制的关键因素的假设。目的1确定Nlrp3介导的信号是否导致肾小管上皮(RTE)细胞损伤，并确定导致这种损伤的信号事件。目的2确定Nlrp3介导的RTE细胞损伤是否需要炎性小体的形成。目的3将确定Nrp3的激活是否主要通过直接(局部)或间接(全身)机制导致肾脏IR损伤。实现国家目标的研究设计和方法：拟议的实验旨在测试RTE细胞凋亡/坏死的诱导，确定Nlrp3介导的损伤所涉及的细胞死亡信号通路，并使用移植模型确定全身损伤介质是否依赖于Nlrp3的激活。基于初步数据，我们研究的重点是确定Nlrp3信号是否独立于其他炎症体成分，这可能确定Nlrp3在RTE细胞中发挥全新的信号作用。项目的健康相关性：如果这项提案的目标得以实现，我们将了解受损组织释放的分子如何激活肾脏中依赖Nlrp3的损伤反应。这一知识对于开发合理的靶向疗法，在预期肾脏缺氧的临床情况下(例如，在供肾供肾移植前对供体肾脏进行预处理)预防缺血性肾损伤至关重要。我们认为，增加对导致缺血性肾损伤的最早事件的了解，对有效预防和治疗这种常见疾病具有最大的希望。

DESCRIPTION (provided by applicant): This study examines how an intracellular pattern recognition receptor called Nlrp3 contributes to acute kidney injury in a murine model of renal ischemia reperfusion (IR) injury. Experimental renal IR injury mimics ischemic acute kidney injury, a major cause of morbidity and mortality in hospitalized patients. Broad/long-term objectives: The long-term goals of the proposed research are to define how Nlrp3 contributes to injurious tissue responses in the kidney. Specific Aims: The specific objective of this proposal is to test the hypothesis that the cytoplasmic PRR Nlrp3 is a key contributor to the pathogenesis of renal IR injury. Aim 1 will determine whether Nlrp3-mediated signals cause renal tubular epithelial (RTE) cell injury and define the signaling events that lead to this injury. Aim 2 will determine whether Nlrp3-mediated RTE cell injury requires inflammasome formation. Aim 3 will determine whether activation of Nrp3 contributes to renal IR injury primarily through direct (local) or indirect (systemic) mechanisms. Research design and methods for achieving the state goals: The proposed experiments are designed to test for induction of RTE cell apoptosis/necrosis, define the cell death signaling pathways involved in Nlrp3- mediated injury and using a transplant model determine whether systemic mediators of injury are dependent upon Nlrp3 activation. Based on preliminary data, a focus of our studies is on determining whether Nlrp3 signals independently of other inflammasome components, which might identify an entirely new signaling role for Nlrp3 in RTE cells. Health relatedness of project: If the aims of this proposal are met, we will learn how molecules released from injured tissue activate Nlrp3-dependent injurious responses in the kidney. This knowledge is crucial for the development of rational targeted therapies for prevention of ischemic kidney injury in clinical situations where renal hypoxia is anticipated (e.g., pretreatment of donor kidneys prior to harvest for transplantation). We believe that increasing our understanding of the earliest events leading to ischemic kidney injury holds the greatest promise for effective prevention and treatment of this common disorder.