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: 8397416
• 负责人: Raghavan Pillai Raju
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/8397416
• 关键词: Accounting; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Cardiac; Cell Survival; Cells; Cessation of life; ChIP-on-chip; Control Animal; Data; Dietary Component; Dose; Down-Regulation; Enhancers; Enzymes; Free Radicals; Functional disorder; Genes; Goals; Grapes; Health; Heart; Hemorrhage; Hemorrhagic Shock; Homologous Gene; Hour; Hypoxia; In Vitro; Injury; Intestines; Ischemia; Knowledge; Left; Left Ventricular Function; Liquid substance; Liver; Longevity; Mating Types; Mediating; Mediator of activation protein; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; NF-kappa B; Organ; Outcome; Oxidative Phosphorylation; Pathway interactions; Performance; Perfusion; Plants; Protein Acetylation; Rattus; Regulation; Reperfusion Injury; Reperfusion Therapy; Resolution; Resuscitation; Resveratrol; Techniques; Testing; Therapeutic; Time; Tissues; Trauma; Ventricular; Work; Yeasts; base; c-myc Genes; cell injury; cytochrome c; cytokine; enzyme activity; functional genomics; heme oxygenase-1; improved; in vitro Model; in vivo; inhibitor/antagonist; mortality; novel; oxidative damage; phytoalexin; phytoalexins; polyphenol; research study; tool; trans-resveratrol

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) establish that resveratrol improves survival and reduces organ injury following T-H. (3) determine the effect of resveratrol treatment on cellular energetics following T-H in the heart and the liver, and (4) identify the mediators and mechanism of T-H injury resolution by resveratrol using in vivo and in vitro models. 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. PUBLIC HEALTH RELEVANCE: T-H injury is a significant health burden as it accounts for up to 40% of trauma-related deaths. Our long-term goal is to develop better therapeutic methods to reduce morbidity and mortality following trauma-hemorrhagic shock. PUBLIC HEALTH RELEVANCE: Hemorrhage accounts for almost half of trauma-related deaths in the United States. Following hemorrhage, fluid resuscitation is employed to restore organ perfusion and reoxygenation. Reoxygenation causes oxidative damage and cell injury. Our objective is to develop better resuscitation methods to reduce tissue damage following hemorrhage. Based upon our preliminary data, we propose that resveratrol, when used as an adjunct to resuscitation fluid, will reduce cell injury following hemorrhage.

描述（由申请人提供）：严重的出血会导致全身缺氧，多器官功能障碍和死亡。流体复苏用于恢复出血性损伤后的器官灌注和重氧。重氧会导致氧化损伤，细胞和器官损伤，并且有必要开发出更好的复苏方法来减少出血后细胞损伤。我们对大鼠线粒体功能基因组学的系统研究导致鉴定出涉及SIRT1的新途径（siR2-SiR2-SiLent交配类型信息调节2）中的新途径。我们的研究表明，创伤性突出（T- H）后SIRT1表达显着下降。我们的初步数据还表明，白藜芦醇（Trans-3,5,4'-Trihydroxystilbene），一种植物甲状腺素抗氧化剂发现了I葡萄和SIRT1活性的增强剂，可减少出血后心脏和肝损伤。因此，我们的目标是确定白藜芦醇可以用作复苏的辅助 流体，出血后。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，白藜芦醇在出血性休克后减少器官损伤，因此可以用作复苏液的辅助。我们将通过追求以下四个特定目的来检验中心假设：（1）优化白藜芦醇作为复苏液的辅助的时间和剂量，（2）确定白藜芦醇可改善生存率并减少T-H后的器官损伤。 （3）确定白藜芦醇处理对心脏和肝脏T-H之后细胞能量的影响，（4）（4）通过使用体内和体外模型来确定白藜芦醇通过白藜芦醇解决T-H损伤的介体和机制。我们将使用最先进的工具和技术，例如线粒体功能基因组学和芯片芯片方法来检验假设。当提出的研究完成后，除了确定白藜芦醇作为复苏液的辅助外，我们还将获得有关与出血损伤有关的分子途径以及抗氧化剂白藜芦醇调节的新知识。公共卫生相关性：T-H受伤是一种重大健康负担，因为它占与创伤有关的死亡的40％。我们的长期目标是开发更好的治疗方法，以降低创伤性造成伤害性休克后的发病率和死亡率。 公共卫生相关性：在美国，出血占与创伤有关的死亡的一半。出血后，采用液体复苏来恢复器官灌注和重氧。重氧会导致氧化损伤和细胞损伤。我们的目标是开发更好的复苏方法，以减少出血后的组织损伤。根据我们的初步数据，我们建议白藜芦醇用作复苏液的辅助，将减少出血后细胞损伤。