Metabolic alterations in hemorrhagic shock

项目摘要 出血性损伤(HI)是45岁以下人群死亡的主要原因，占 几乎一半与创伤相关的死亡。失血性休克导致全身缺氧，营养不良 可能导致多器官的关键生化途径的剥夺和失调 功能障碍综合症和死亡。线粒体功能下降是出血性疾病的一个标志 已知休克和线粒体功能增强有助于改善HI后的预后 动物模型..我们的目标是通过确定 HI后调节代谢动态平衡的内源性机制。我们的中央 假设AMPK-SIRT1轴参与了出血性损伤后线粒体功能的调节。 我们的目标是1)使用转基因小鼠和小分子激活剂和 与线粒体功能相关的代谢途径中涉及的关键蛋白质的抑制物 可以确定特定的靶点来治疗HI和其他低流量情况；2)确定 PDE-AMPK介导的线粒体功能调控和SIRT1直接调控 3)确定烟酸调节SIRT1活性和线粒体的机制 HI后的功能；4)通过确定临界状态来确定改善线粒体功能的方法 调节细胞能量的代谢途径，以及5)开发新的治疗策略 减少HI后的代谢失衡。Aim 1检验AMPK-SIRT1轴是 对改善线粒体功能和HI后的存活率至关重要。我们将确定 缺氧缺血时PDE-AMPK通路与SIRT1的直接调控我们将确定分子 通过测试关键代谢指标，如NAD/NADH比率，p-AMPK， CaMKK和PGC-1在HI后和用激活或抑制KEY的药物治疗后 参与这些途径的蛋白质。Aim 2验证了烟酸可提高术后存活率的假设 Hi通过增加细胞内NAD+。我们建议确定HI和HI中的代谢检查点 延长生命的新治疗策略。这项拟议的研究与NIH的这一部分相关 与发展基础知识有关的任务，这可能有助于减少 人类疾病的负担。这项研究的结果将具有重要意义，因为 从这项研究中获得的基本知识有望推动促进健康的方法 活着。

Project Summary Hemorrhagic injury (HI) is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. Hemorrhagic shock leads to whole body hypoxia, nutrient deprivation and dysregulation of critical biochemical pathways that may result in multiple organ dysfunction syndrome and death. Mitochondrial functional decline is a hallmark of hemorrhagic shock and enhanced mitochondrial function is known to contribute to better outcome following HI in animal models.. Our goal is to reduce the incidence of death due to HI and shock by identifying endogenous mechanisms that modulate metabolic homeostasis following HI. Our central hypothesis is that AMPK-SIRT1 axis modulate mitochondrial function following Hemorrhagic injury. Our objectives are to 1) use genetically modified mice and both small molecule activators and inhibitors of critical proteins involved in metabolic pathways linked to mitochondrial function so that specific targets can be identified to treat HI and other low flow conditions; 2) determine the roles of PDE-AMPK-mediated regulation and direct SIRT1 regulation in mitochondrial functional modulation following HI; 3) Identify mechanism by which niacin modulates SIRT1 activity and mitochondrial function following HI; 4) identify methods to improve mitochondrial function by determining critical metabolic pathways that regulate cellular energetics, and 5) develop novel therapeutic strategies to reduce the metabolic imbalance following HI. Aim 1 tests the hypothesis that AMPK-SIRT1 axis is critical in improving mitochondrial function and survival following HI. We will determine the role of the PDE-AMPK pathway and direct SIRT1 regulation in HI. We will determine the molecular players in these pathways by testing key metabolic measures such as NAD/NADH ratio, p-AMPK, CaMKK and Pgc-1 following HI, and after treatment with agents that activate or inhibit key proteins involved in these pathways. Aim 2 tests the hypothesis that niacin improves survival after HI by augmenting intracellular NAD+. We propose to identify the metabolic check points in HI and new therapeutic strategies to prolong life. The proposed research is relevant to that part of NIH’s mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. The outcome of this research will be significant because the fundamental knowledge gained from this study is expected to advance methods to promote healthy living.