Role of NOD2 in Acute Lung Injury Following Ischemic Kidney Injury

NOD2 在缺血性肾损伤后急性肺损伤中的作用

• 批准号: 10683703
• 负责人: Sean Edward DeWolf
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683703
• 关键词: Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Acute Respiratory Distress Syndrome; Alveolar; Binding; Cells; Cellular biology; Clinical; Cytoplasm; Data; Development; Edema; Endothelial Cells; Endothelium; Environment; Epithelial Cells; Event; Exposure to; Family; Family member; Foundations; Funding; Future; Gases; Grant; Hospitalization; Human; Immune; Immune response; Immune signaling; Immunologic Receptors; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Intensive Care Units; K-Series Research Career Programs; Kidney; Knock-out; Knowledge; Laboratories; Link; Lung; MAP Kinase Gene; Membrane; Mentors; Modeling; Molecular; Molecular Biology; Mus; Natural Immunity; Necrosis; Nucleotides; Pathogenesis; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Permeability; Physicians; Play; Production; Renal tubule structure; Reperfusion Injury; Research Institute; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Therapeutic; Time; Training; Tubular formation; Up-Regulation; Vascular Endothelial Cell; Ventilator; Work; career; cell injury; cell type; clinical training; cytokine; effective therapy; experimental study; improved; in vivo; in vivo Model; innate immune mechanisms; innate immune pathways; interest; lung injury; lung microvascular endothelial cells; mortality; mouse model; novel therapeutic intervention; pathogen; pathogenic microbe; pharmacologic; receptor; renal ischemia; response; skills; therapeutic target

Abstract Acute respiratory distress syndrome (ARDS) is characterized by pulmonary endothelial inflammation that leads to alveolar edema and poor gas exchange. It has a high mortality, and effective treatment options to date are limited. Acute kidney injury increases the mortality from ARDS and there is substantial evidence that kidney injury can directly worsen the lung injury. The mechanisms underlying this kidney-lung interaction are not well understood and could hold therapeutic potential. Following renal ischemia reperfusion injury (IRI), endogenous stress molecules (DAMPs or damage associated molecular patterns) are released from dying renal tubular cells and bind to pathogen recognition receptors (PRRs) on neighboring cells, initiating an inflammatory cascade that worsens renal injury. In preliminary data we have already seen that renal derived DAMPs cause upregulation of inflammatory cytokines and MAPK activation in uninjured renal tubular epithelial cells. Expanding this model to kidney-lung cross talk, human pulmonary endothelial cells exposed to renal tubule-derived DAMPs were found to upregulate inflammatory cytokines and specific PRRs. These preliminary data also revealed that NOD2, a PRR known to play a key role in acute kidney injury, was disproportionately upregulated when compared to other PRRs. Our lab has previously shown that NOD2 knockout protects mice from renal IRI, and preliminary data suggest that inhibition of NOD2 via pharmacologic blockade decreases the inflammatory response of renal tubular epithelial cells to renal derived DAMPs. The hypothesis of this proposal is that NOD2 plays a critical role in lung injury following renal IRI by inducing proinflammatory responses in the pulmonary microendothelium, contributing to ARDS. Given the importance of microvascular endothelial cells in the pathogenesis of ARDS, this proposal focuses on the role of NOD2 on injurious responses in pulmonary microvascular endothelial cells after renal IRI. I will focus on the canonical NOD2 signaling pathways in pulmonary microvascular endothelial cells in response to renal derived DAMPs and also use an in vivo model of renal IRI to correlate NOD2 activation with lung injury. This proposal will provide important new knowledge and skill sets needed to set the stage for the development of my career as a physician-scientist. The work proposed in this application will be conducted in a rich training environment at UC San Diego and the Scripps Research Institute with an exceptional interdisciplinary mentoring team including leaders in the field of innate immunity, endothelial cell biology, and ARDS.

摘要 急性呼吸窘迫综合征(ARDS)的特征是肺内皮细胞炎症导致 肺泡水肿和气体交换不良。它的死亡率很高，到目前为止有效的治疗选择是 有限的。急性肾损伤会增加ARDS的死亡率，有大量证据表明，肾脏 损伤可直接加重肺损伤。这种肾肺相互作用的机制还不是很清楚。 理解并具有治疗潜力。肾缺血再灌注损伤(IRI)后内源性 应激分子(潮湿或损伤相关的分子模式)从死亡的肾小管细胞中释放出来。 并与邻近细胞上的病原体识别受体(PRR)结合，启动炎症级联反应 会加重肾脏损伤。在初步数据中，我们已经看到肾衍生的阻滞剂会导致 未损伤肾小管上皮细胞中的炎性细胞因子和MAPK激活。将此模式扩展为 肾肺串扰，人肺内皮细胞暴露于肾小管源性阻尼剂 上调炎性细胞因子和特异性PRR。这些初步数据还显示，NOD2，a 已知在急性肾损伤中起关键作用的PRR，与其他 PRRS。我们的实验室之前已经证明，NOD2基因敲除可以保护小鼠免受肾脏IRI的影响，初步数据 提示通过药物阻断抑制NOD2可减少肾脏的炎症反应 肾小管上皮细胞至肾源性受潮。这一提议的假设是NOD2起着关键作用 在肾IRI后的肺损伤中，通过诱导肺微内皮细胞的促炎反应， 对急性呼吸窘迫综合征有贡献。鉴于微血管内皮细胞在ARDS发病机制中的重要性，这 建议侧重于NOD2在肺微血管内皮细胞损伤反应中的作用 肾IRI。我将集中在肺微血管内皮细胞中典型的NOD2信号通路。 并使用肾脏IRI的活体模型将NOD2的激活与 肺损伤。这项提议将提供重要的新知识和技能，为 我作为一名内科科学家的职业发展。本申请书中建议的工作将在 加州大学圣地亚哥分校和斯克里普斯研究所丰富的培训环境，具有卓越的 跨学科指导团队，包括先天免疫、内皮细胞生物学和 阿兹。