Role of Nlrp3 in Ischemic Organ Injury

描述（由申请人提供）：本研究检查了称为Nlrp 3的细胞内模式识别受体如何在肾缺血再灌注（IR）损伤的小鼠模型中促进急性肾损伤。实验性肾IR损伤模拟缺血性急性肾损伤，缺血性急性肾损伤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Nlrp 3如何促进肾脏中的损伤组织反应。具体目标：本提案的具体目的是检验细胞质PRR Nlrp 3是肾IR损伤发病机制的关键因素的假设。目的1将确定Nlrp 3介导的信号是否引起肾小管上皮细胞（RTE）损伤，并定义导致这种损伤的信号事件。目的2将确定Nlrp 3介导的RTE细胞损伤是否需要炎性小体形成。目的3将确定Nrp 3的激活是否主要通过直接（局部）或间接（全身）机制导致肾IR损伤。研究设计和实现国家目标的方法：所提出的实验旨在测试诱导RTE细胞凋亡/坏死，定义参与Nlrp 3介导的损伤的细胞死亡信号通路，并使用移植模型确定损伤的全身介质是否依赖于Nlrp 3激活。基于初步数据，我们的研究重点是确定Nlrp 3信号是否独立于其他炎性体组分，这可能会确定Nlrp 3在RTE细胞中的全新信号作用。项目的健康相关性：如果这个提议的目标得到满足，我们将了解从受损组织释放的分子如何激活肾脏中Nlrp 3依赖的损伤反应。这一知识对于开发合理的靶向治疗以预防在预期肾缺氧的临床情况下的缺血性肾损伤是至关重要的（例如，在收获用于移植之前对供体肾进行预处理）。我们相信，增加我们对缺血性肾损伤的最早期事件的了解，对于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.