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: 10417247
• 负责人: Katherine J Kelly
• 金额: $ 19.81万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417247
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Biological; Blood Platelets; Caring; Cell Therapy; Cell Transplantation; Cells; Cessation of life; Chronic Kidney Failure; Creatinine; Data; Development; Disease; Effectiveness; End stage renal failure; Endothelial Cells; Epidemic; Epithelial Cells; Etiology; Failure; Functional disorder; Future; Goals; Health; Hospitalization; Hour; Hypoxia; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Intensive Care; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Malignant Neoplasms; Mediator; 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; biological adaptation to stress; catalase; cytokine; effective therapy; evidence base; exosome; functional improvement; immune cell infiltrate; improved; 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.

缺血性肾脏损伤很常见，导致急性肾脏损伤（AKI），导致 慢性肾脏疾病（CKD）的流行和其他病因的CKD进展 肾脏疾病和移植功能障碍。 AKI发生在多达三分之二的重症监护患者中 全球五分之一的住院成年人中有1个，但目前尚无有效的治疗。很遗憾， 几十年来，死亡率并未显着改善。因此，需要新的方法。尽管 理解病理生理学和肾脏替代疗法的巨大进展，AKI是 与不可接受的高死亡率有关。我们和其他人已经记录了 肾脏缺血后伤害的炎症反应。此外，我们发现外泌体 即使在给予后，也可以改善肾功能，结构，炎症和氧化应激 建立了肾衰竭。肾脏炎症的机制和外泌体受益的机制， 但是，不太了解。该建议旨在通过检查 来自炎症和氧化应激的不同来源的外泌体。 我们的长期目标是开发有效疗法以改善急性的预后 肾脏受伤。该应用的目的是定义肾外泌体的机制 缺血/再灌注损伤后减少炎症和氧化应激。我们的中心 假设是肾外泌体为肾脏缺血性损伤提供了多方面的疗法， 增加肾脏超氧化物，过氧化氢酶以及抗炎细胞因子。此外，我们认为 皮肤和血小板外泌体不具有保护性，使我们能够定义特定的有益 外泌体货物。根据我们的初步数据，我们提出以下目的，运用良好 建立的模型： 1。定义来自不同来源的外泌体的疗效，肾功能，肾功能， 炎症和氧化应激。 2。确定外泌体对低氧促炎转化的影响 在许多因素可以控制的系统中，肾小管和内皮细胞。 3。比较保护性和保护性和抗氧化作用的货物和抗氧化作用 无效的外泌体，包括肾脏，皮肤，血小板和间质干细胞外泌体。 在这项工作结束时，我们希望定义关键的炎症和氧化性。 缺血性肾损伤的应力介体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，因为它们将提供强大的基于证据的 进一步开发潜在疗法以改善AKI预后的原则证明。