Resveratrol as an adjunct to resuscitation fluid following hemorrhage injury

描述(申请人提供)：严重出血可导致全身缺氧、多器官功能障碍和死亡。液体复苏用于恢复出血性损伤后器官的灌流和复氧。复氧导致氧化损伤和细胞和器官损伤，需要开发更好的复苏方法来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发现了一条涉及Sirt1(Sirt2的哺乳动物同源基因-沉默交配型信息调节2)参与失血性损伤的新途径。我们的研究表明，创伤-出血(T-H)后Sirt1的表达显著下降。我们的初步数据还表明，白藜芦醇(反式-3，5，4‘-三羟基二苯乙烯)，一种在葡萄中发现的植物保鲜蛋白抗氧化剂，以及Sirt1活性增强剂，可以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作为复苏的辅助手段 出血后的体液。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，白藜芦醇可以减轻失血性休克后的器官损伤，因此可以作为复苏液的辅助物质。我们将通过追求以下四个具体目标来检验中心假说：(1)优化白藜芦醇作为复苏液辅助药物的时间和剂量，(2)确定白藜芦醇治疗对心脏和肝脏T-H后细胞能量学的影响，(3)确定白藜芦醇缓解T-H损伤的介质和机制，以及(4)建立白藜芦醇减少T-H后器官损伤并提高存活率的机制。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芯片方法来验证这一假说。当拟议的研究完成后，除了将白藜芦醇确定为复苏液的辅助物质外，我们还将获得有关出血损伤的分子途径以及抗氧化剂白藜芦醇对其调节的新知识。

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.