Role of NOD2 in ischemia reperfusion injury

NOD2在缺血再灌注损伤中的作用

• 批准号: 9750718
• 负责人: Dianne B Mckay
• 金额: $ 43.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750718
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Anaerobic Bacteria; Back; Binding; Blood flow; Cell Death; Cell Death Signaling Process; Cells; Clinical; Complex; Cytoplasm; Data; Development; Epithelial; Epithelial Cells; Evaluation; Event; Exposure to; Family; Family member; Functional disorder; Goals; Health; Hypoxia; Immune; Immune response; Immunologic Receptors; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Innate Immune System; Kidney; Kidney Transplantation; Knowledge; Laboratories; Lead; Learning; Ligands; Ligation; Link; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolism; Modeling; Molecular Target; Necrosis; Nucleotides; Pathologic; Pathway interactions; Patients; Pattern Recognition; Pattern recognition receptor; Phase; Phylogenetic Analysis; Play; Prevention therapy; Preventive; Reperfusion Injury; Reperfusion Therapy; Research; Research Design; Research Methodology; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; System; Testing; Therapeutic; Tissues; Toll-like receptors; Treatment Efficacy; Tubular formation; Vascular blood supply; cell injury; cell type; experimental study; in vivo; injured; interest; marenostrin; novel; pathogen; pathogenic microbe; prevent; programs; receptor; renal ischemia; response; response to injury; restoration; targeted treatment; transplant model; tubular necrosis

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.

项目摘要：该建议研究关键的细胞质先天免疫受体NOD2， 导致肾脏缺血再灌注（IR）损伤。该项目对于缺血性肾脏非常重要 受伤，就像住院的患者经常发生的那样。 广泛/长期目标：拟议研究的长期目标是定义NOD2 肾脏有害组织反应。 具体目的：该提案的具体目标是检验细胞质模式的假设 识别受体NOD2是肾脏IR损伤引起的肾小管上皮损伤的关键因素。 AIM 1询问NOD2激活是否指导肾小管上皮细胞损伤，定义信号事件 这导致了这种伤害，并确定NOD2阻断是否阻止了肾小管上皮损伤。 AIM 2询问NOD2的激活是否主要通过直接（局部）导致缺血性肾脏损伤 或间接（全身）机制。 实现既定目标的研究设计和方法：AIM 1将测试NOD2的连接方式 伤害肾小管上皮细胞，NOD2激活刺激是否指导RTE细胞的模式 损伤，从坏死细胞释放的分子如何激活NOD2介导的健康RTE损伤 细胞，以及是否可以通过阻断NOD2或上游激活之一来阻止RTE细胞损伤 途径。体内IR损伤结合了其他组织损伤的介质，例如炎症，因此AIM 2 专注于NOD2激活是否通过将局部（肾脏损伤）与 系统性（炎症）。直接（局部，肾脏特异性）效应与间接（全身）效应分开 在肾脏移植模型中，在野外研究了NOD2 - / - 移植肾脏的损伤反应 类型（WT）宿主和在NOD2 - / - 主机中研究的WT肾脏损伤。 项目的健康相关性：如果满足该提案的目的，我们将了解分子如何发布 从受伤的组织中激活肾脏中的NOD2依赖性有害反应。这些知识对 临床预防或改善肾脏IR损伤的理性靶疗法的发展 预计缺氧的情况。专注于缺血性肾脏损伤的最早事件 有效治疗策略的最大希望。