Resveratrol as an adjunct to resuscitation fluid following hemorrhage injury

描述（由申请人提供）：严重出血导致全身缺氧，多器官功能障碍，死亡。液体复苏用于恢复出血性损伤后的器官灌注和再氧合。再氧化引起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 （sir2沉默交配型信息调控2的哺乳动物同源物）的新途径。我们的研究表明，创伤性出血后Sirt1表达显著下降（T- H）。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）是葡萄中发现的一种植物抗菌素抗氧化剂，也是Sirt1活性的增强剂，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

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.