Anti-inflammatory actions of exosomes in the postischemic kidney

外泌体在缺血后肾脏中的抗炎作用

• 批准号: 10307419
• 负责人: Katherine J Kelly
• 金额: $ 23.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-03 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307419
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Biological; Blood Platelets; Cell Therapy; Cell Transplantation; Cells; Cessation of life; Chronic Kidney Failure; Creatinine; Data; Development; Disease; Disease Progression; Effectiveness; End stage renal failure; Endothelial Cells; Epidemic; Epithelial Cells; Etiology; Failure; Functional disorder; Future; Goals; Health; Hour; Hypoxia; Immune; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Intensive Care; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Malignant Neoplasms; Mediator of activation protein; Medical; Mesenchymal Stem Cells; Modeling; Organ; Organ Transplantation; Oxidative Stress; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Pre-Clinical Model; Recovery; Renal Replacement Therapy; Renal function; Reperfusion Injury; Research; Role; Skin; Source; Structure; Superoxide Dismutase; Superoxides; System; Therapeutic; Transplantation; Tubular formation; Work; base; biological adaptation to stress; catalase; cytokine; effective therapy; evidence base; exosome; improved; improved functioning; improved outcome; ischemic injury; meetings; mortality; novel strategies; oxidation; protective effect; renal hypoxia; renal ischemia; stem cell exosomes

Ischemic renal injury is common, causes acute kidney injury (AKI), contributes to the epidemic of chronic kidney disease (CKD) and progression of CKD of other etiologies to end stage renal disease and to transplant dysfunction. AKI occurs in up to two thirds of intensive care patients and 1 in 5 hospitalized adults worldwide, yet there is currently no effective therapy. Unfortunately, mortality has not improved significantly in decades. Thus, new approaches are needed. Despite large advances in understanding pathophysiology, and in renal replacement therapy, AKI is associated with unacceptably high mortality. We and others have documented the role of inflammatory responses in injury following renal ischemia. In addition, we have found that exosomes can improve renal function, structure, inflammation and oxidative stress, even when given after renal failure is established. The mechanisms of renal inflammation and benefit with exosomes, however, are not well understood. This proposal aims to fill those gaps by examining the effects of exosomes from different sources on inflammation and oxidative stress in the postischemic kidney. Our long-term goal is the development of effective therapies to improve outcomes in acute kidney injury. The objective of this application is defining the mechanisms by which renal exosomes decrease inflammation and oxidative stress following ischemia/reperfusion injury. Our central hypothesis is that renal exosomes provide a multi-faceted therapy for renal ischemic injury, increasing renal superoxide and catalase and anti-inflammatory cytokines. Furthermore, we posit that skin and platelet exosomes are not protective, allowing us to define specific beneficial exosomal cargo. Based on our preliminary data, we propose the following aims, employing out well established model: 1. To define the efficacy of exosomes from different sources on postischemic, renal function, inflammation and oxidative stress. 2. To determine the effect of exosomes on the proinflammatory transformation of hypoxic kidney tubular and endothelial cells in a system in which many factors can be controlled. 3. To compare cargo and the anti-inflammatory and anti-oxidation effects of protective and ineffective exosomes, including renal, skin, platelet and mesenchymal stem cell exosomes. At the conclusion of this work, we expect to have defined the key inflammatory and oxidative stress mediators of ischemic renal injury and the exosomal cargo that improve function. The results are expected to have a significant positive impact in that they will provide the strong evidence-based proof of principle for further development of potential therapies to improve outcomes in AKI.

缺血性肾损伤很常见，会导致急性肾损伤 (AKI)，导致 慢性肾脏病 (CKD) 的流行以及其他病因的 CKD 进展至终末期 肾脏疾病和移植功能障碍。多达三分之二的重症监护患者会发生 AKI 全球有五分之一的住院成人患有此病，但目前尚无有效的治疗方法。很遗憾， 几十年来，死亡率并没有显着改善。因此，需要新的方法。尽管 在理解病理生理学和肾脏替代疗法方面取得了巨大进展，AKI 与不可接受的高死亡率相关。我们和其他人已经记录了以下角色的作用： 肾缺血损伤后的炎症反应。此外，我们还发现外泌体 可以改善肾功能、结构、炎症和氧化应激，即使是在 肾功能衰竭成立。肾脏炎症的机制和外泌体的益处， 然而，并没有得到很好的理解。该提案旨在通过审查以下措施的影响来填补这些空白： 不同来源的外泌体对缺血后肾脏炎症和氧化应激的影响。 我们的长期目标是开发有效的疗法来改善急性发作的结果 肾损伤。本申请的目的是确定肾外泌体的机制 减少缺血/再灌注损伤后的炎症和氧化应激。我们的中央 假设肾外泌体为肾缺血性损伤提供多方面的治疗， 增加肾脏超氧化物和过氧化氢酶以及抗炎细胞因子。此外，我们假设 皮肤和血小板外泌体没有保护作用，这使我们能够定义特定的有益效果 外泌体货物。根据我们的初步数据，我们提出以下目标，充分利用 建立模型： 1. 确定不同来源的外泌体对缺血后、肾功能、 炎症和氧化应激。 2. 确定外泌体对缺氧促炎转化的影响 肾小管和内皮细胞处于一个系统中，其中许多因素都可以控制。 3. 比较货物以及保护剂和抗氧化剂的抗炎和抗氧化作用 无效的外泌体，包括肾、皮肤、血小板和间充质干细胞外泌体。 在这项工作结束时，我们希望能够定义关键的炎症和氧化 缺血性肾损伤的应激介质和改善功能的外泌体货物。结果 预计将产生重大的积极影响，因为它们将提供强有力的基于证据的 进一步开发潜在疗法以改善 AKI 结局的原理证明。