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

基本信息

批准号：
8517149
负责人：
Raghavan Pillai Raju
金额：
$ 9.3万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-11-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517149
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 Heart Injuries 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 liver injury mortality novel oxidative damage phytoalexin phytoalexins polyphenol research study tool trans-resveratrol

项目摘要

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.

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) 确定白藜芦醇可提高 T-H 后的生存率并减少器官损伤。 (3) 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，以及 (4) 使用体内和体外模型确定白藜芦醇消除 T-H 损伤的介质和机制。我们将使用线粒体功能基因组学和 ChIP 芯片方法等最先进的工具和技术来检验这一假设。当拟议的研究完成后，除了确定白藜芦醇作为复苏液的辅助剂外，我们还将获得有关出血损伤的分子途径及其抗氧化剂白藜芦醇调节的新知识。