Resveratrol as an adjunct to resuscitation fluid following hemorrhage injury

白藜芦醇作为失血性损伤后复苏液的辅助剂

• 批准号: 8825553
• 负责人: Raghavan Pillai Raju
• 金额: $ 18.01万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825553
• 关键词: Resveratrol; adjunct; resuscitation; fluid; following

DESCRIPTION (provided by applicant): Severe hemorrhage causes whole body hypoxia, multiple organ dysfunction and death. Fluid resuscitation is employed to restore organ perfusion and reoxygenation following hemorrhagic injury. Reoxygenation causes oxidative damage and cell and organ injury and there is a need to develop better resuscitation methods to reduce cell injury following hemorrhage. Our systematic study of mitochondrial functional genomics in the rat resulted in the identification of a novel pathway involving Sirt1 (mammalian homolog of sir2-silent mating type information regulation 2) in hemorrhagic injury. Our studies demonstrated a significant decline in Sirt1 expression following trauma-hemorrhage (T- H). Our preliminary data also indicate that resveratrol (trans-3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found i grapes, and an enhancer of Sirt1 activity, reduces heart and liver injury following hemorrhage. Our objective is therefore to establish that resveratrol can be used as an adjunct to resuscitation fluid, following hemorrhage. We will also determine the molecular basis of tissue injury and resveratrol-mediated protection following T-H. Our hypothesis is that resveratrol reduces organ injury following hemorrhagic shock and therefore it can be used as an adjunct to resuscitation fluid. We will test the central hypothesis by pursuing the following four Specific Aims: (1) optimize the time and dose of resveratrol as an adjunct to resuscitation fluid, (2) determine the effect of resveratrol treatment on cellular energetics following T-H in the heart and the liver, (3 identify the mediators and mechanism of T-H injury resolution by resveratrol and (4) establish that resveratrol reduces organ injury and improve survival following T-H. We will use state-of-the-art tools and techniques such as mitochondrial functional genomics and ChIP-chip method to test the hypothesis. When the proposed studies are completed, in addition to identifying resveratrol as an adjunct to resuscitation fluid, we would have also gained new knowledge on molecular pathways involved in hemorrhage injury and their modulation by the antioxidant resveratrol.

描述（申请人提供）：严重失血导致全身缺氧、多器官功能障碍甚至死亡。液体复苏用于恢复失血性损伤后的器官灌注和再氧合。再氧合会导致氧化损伤以及细胞和器官损伤，因此需要开发更好的复苏方法以减少出血后的细胞损伤。我们对大鼠线粒体功能基因组学的系统研究导致了出血性损伤中涉及 Sirt1（sir2-沉默交配型信息调节 2 的哺乳动物同源物）的新途径的鉴定。我们的研究表明，创伤出血 (TH) 后 Sirt1 表达显着下降。我们的初步数据还表明，白藜芦醇（反式 3,5,4'-三羟基芪）是葡萄中发现的一种植物抗氧化剂，也是 Sirt1 活性的增强剂，可减少出血后的心脏和肝脏损伤。因此，我们的目标是确定白藜芦醇可以用作复苏的辅助手段 出血后的液体。我们还将确定 T-H 后组织损伤和白藜芦醇介导的保护的分子基础。我们的假设是，白藜芦醇可以减少失血性休克后的器官损伤，因此它可以用作复苏液的辅助剂。我们将通过追求以下四个具体目标来检验中心假设：(1) 优化白藜芦醇作为复苏液辅助剂的时间和剂量，(2) 确定白藜芦醇治疗对心脏 T-H 后细胞能量学的影响，以及肝脏，（3 确定白藜芦醇解决 T-H 损伤的介质和机制，并且（4）确定白藜芦醇可减少器官损伤并提高 T-H 后的生存率。我们将使用最先进的工具和技术，如线粒体功能基因组学和 ChIP 芯片方法来检验这一假设。当拟议的研究完成时，除了确定白藜芦醇作为复苏液的辅助剂外，我们还将获得新的成果。有关出血损伤的分子途径及其通过抗氧化剂白藜芦醇的调节的知识。