Role of NOD2 in ischemia reperfusion injury

项目概述：该提案研究了关键的细胞质先天免疫受体NOD 2， 导致肾缺血再灌注（IR）损伤。该项目对缺血性肾脏具有重要意义 这是一种常见于住院患者的疾病。 广泛/长期目标：拟议研究的长期目标是确定NOD 2 会导致肾脏的有害组织反应。 具体目标：本提案的具体目标是检验细胞质模式 识别受体NOD 2是由肾IR损伤诱导的肾小管上皮损伤的关键贡献者。 目的1：探讨NOD 2的激活是否直接导致肾小管上皮细胞损伤， 导致这种损伤，并确定是否NOD 2阻断防止肾小管上皮细胞损伤。 目的2询问NOD 2的激活是否主要通过直接（局部） 或间接（系统）机制。 研究设计和实现所述目标的方法：目标1将测试NOD 2的连接如何 损伤肾小管上皮细胞，NOD 2激活刺激是否指导RTE细胞的模式 损伤，从坏死细胞（DAMP）释放的分子如何激活NOD 2介导的健康RTE损伤 细胞，以及RTE细胞损伤是否可以通过阻断NOD 2或其上游激活之一来阻断。 途径。体内IR损伤包括其他组织损伤介质，如炎症，因此目的2 关注NOD 2激活是否在肾脏中发挥更广泛的作用，将局部（肾损伤）与 全身性（炎症）。直接（局部，肾脏特异性）效应与间接（全身）效应分开 在肾移植模型中，在野生动物中研究NOD 2-/-移植肾的损伤反应， 型（WT）宿主，以及在NOD 2-/-宿主中研究的WT肾损伤。 项目的健康相关性：如果本提案的目标得到满足，我们将了解分子如何释放 从受损组织中释放的N 0 D 2激活肾脏中的NOD 2依赖性损伤反应。这些知识对于 在临床上开发合理的靶向治疗方法预防或改善肾IR损伤 在缺氧的情况下。关注缺血性肾损伤的早期事件， 有效治疗策略的最大希望。

Project Summary: This proposal studies how a key cytoplasmic innate immune receptor, NOD2, contributes to renal ischemia reperfusion (IR) injury. The project is highly significant for ischemic kidney injury, as occurs frequently in hospitalized patients. Broad/long-term objectives: The long-term goals of the proposed research are to define how NOD2 contributes to injurious tissue responses in the kidney. Specific Aims: The specific objective of this proposal is to test the hypothesis that the cytoplasmic pattern recognition receptor NOD2 is a key contributor to renal tubular epithelial damage induced by renal IR injury. Aim 1 asks whether NOD2 activation directs renal tubular epithelial cell injury, defines the signaling events that lead to this injury, and determines whether NOD2 blockade prevents renal tubular epithelial injury. Aim 2 asks whether activation of NOD2 contributes to ischemic renal injury primarily through direct (local) or indirect (systemic) mechanisms. Research Design and Methods for Achieving the Stated Goals: Aim 1 will test how ligation of NOD2 injures renal tubular epithelial cells, whether the NOD2 activating stimulus directs the mode of RTE cell injury, how molecules released from necrotic cells (DAMPs) activate NOD2-mediated injury of healthy RTE cells, and whether RTE cell injury can be blocked by either blocking NOD2 or one of its upstream activating pathways. In vivo IR injury incorporates other mediators of tissue injury, such as inflammation, so aim 2 focus on whether NOD2 activation plays a broader role in the kidney by separating local (kidney injury) from systemic (inflammation). Direct (local, kidney specific) effects are separated from indirect (systemic) effects in a kidney transplant model where injury responses of the NOD2-/- transplanted kidney are studied in a wild type (WT) host, and WT kidney injury studied in a NOD2-/- host. Health Relatedness of Project: If the aims of this proposal are met we will learn how molecules released from injured tissue activate NOD2-dependent injurious responses in the kidney. This knowledge is crucial for the development of rational target therapies for prevention or amelioration of renal IR 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.