Metabolic alterations in hemorrhagic shock

失血性休克的代谢改变

• 批准号: 9906904
• 负责人: Raghavan Pillai Raju
• 金额: $ 29.26万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906904
• 关键词: Aftercare; Age; Animal Model; Biochemical Pathway; CaM kinase I activator; Cause of Death; Cells; Cessation of life; Complex; Consequentialism; Embryo; Experimental Models; Fibroblasts; Generations; Goals; Hemodilution; Hemorrhage; Hemorrhagic Shock; Homeostasis; Hypoxia; Incidence; Injury; Knock-out; Knockout Mice; Knowledge; Life; Link; Liquid substance; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Methods; Mission; Mitochondria; Modeling; Molecular; Multiple Organ Failure; Mus; NADH; Nicotinic Acids; Outcome; Outcomes Research; Pathway interactions; Proteins; Rattus; Regulation; Research; Resuscitation; Resveratrol; Role; Rolipram; SIRT1 gene; Shock; Testing; Therapeutic; Tissues; Transgenic Mice; Trauma; United States National Institutes of Health; Wild Type Mouse; base; beta-Hydroxybutyrate; functional decline; human disease; improved; inhibitor/antagonist; mitochondrial dysfunction; novel therapeutic intervention; novel therapeutics; nutrient deprivation; oxidative damage; prevent; receptor; small molecule

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.

项目概要 出血性损伤 (HI) 是 45 岁以下人群死亡的主要原因 几乎一半的死亡与创伤有关。失血性休克导致全身缺氧、营养不良 关键生化途径的剥夺和失调可能导致多器官功能障碍 功能障碍综合征和死亡。线粒体功能下降是出血性疾病的标志 已知休克和线粒体功能增强有助于 HI 后获得更好的结果 动物模型..我们的目标是通过确定 HI 后调节代谢稳态的内源性机制。我们的中央 假设 AMPK-SIRT1 轴在失血性损伤后调节线粒体功能。 我们的目标是 1) 使用转基因小鼠和小分子激活剂 参与与线粒体功能相关的代谢途径的关键蛋白质的抑制剂 可以确定治疗 HI 和其他低流量病症的具体目标； 2）确定角色 线粒体功能调节中 PDE-AMPK 介导的调节和直接 SIRT1 调节 HI 后； 3) 确定烟酸调节 SIRT1 活性和线粒体的机制 HI 后的功能； 4) 通过确定关键点来确定改善线粒体功能的方法 调节细胞能量的代谢途径，5) 开发新的治疗策略 减少 HI 后的代谢失衡。目标 1 检验 AMPK-SIRT1 轴是的假设 对于改善 HI 后的线粒体功能和生存至关重要。我们将确定角色 HI 中的 PDE-AMPK 通路和直接 SIRT1 调节。我们将确定分子 通过测试关键代谢指标（例如 NAD/NADH 比率、p-AMPK、 HI 后以及使用激活或抑制关键药物治疗后的 CaMKK 和 Pgc-1 参与这些途径的蛋白质。目标 2 检验烟酸可提高术后生存率的假设 HI 通过增加细胞内 NAD+ 来实现。我们建议确定 HI 中的代谢检查点 延长生命的新治疗策略。拟议的研究与 NIH 的该部分相关 与发展基础知识有关的使命可能有助于减少 人类疾病的负担。这项研究的结果将具有重大意义，因为 从这项研究中获得的基础知识预计将有助于推进促进健康的方法 活的。

项目成果

Rapid senescence-like response after acute injury.

• DOI: 10.1111/acel.13201
• 发表时间: 2020-09
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Chu X;Wen J;Raju RP
• 通讯作者: Raju RP