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.

项目摘要 出血性损伤（HI）是45岁以下人群死亡的主要原因， 几乎一半的创伤相关死亡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个器官 功能障碍综合征和死亡。线粒体功能下降是出血性 已知休克和线粒体功能增强有助于HI后更好的结果。 动物模型我们的目标是通过识别 调节HI后代谢稳态的内源性机制。我们的中央 假设AMPK-SIRT 1轴调节出血性损伤后线粒体功能。 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， 可以确定特定的目标，以治疗HI和其他低流量条件; 2）确定 PDE-AMPK介导的调节和SIRT 1直接调节线粒体功能 3）确定烟酸调节SIRT 1活性和线粒体膜电位的机制。 功能; 4）通过确定关键的线粒体功能来确定改善线粒体功能的方法 调节细胞能量学的代谢途径，以及5）开发新的治疗策略， 减少HI后的代谢失衡。目标1检验AMPK-SIRT 1轴是 在改善HI后线粒体功能和存活率方面至关重要。我们将决定 PDE-AMPK通路和SIRT 1的直接调节。我们将确定 通过测试关键的代谢指标，如NAD/NADH比率，p-AMPK， 在HI后和用激活或抑制关键激酶的试剂治疗后， 参与这些途径的蛋白质。目的2检验烟酸改善术后生存率的假设 HI通过增加细胞内NAD+。我们建议确定HI中的代谢检查点， 新的治疗策略来延长生命。这项拟议中的研究与NIH的这一部分有关。 使命，涉及发展基础知识，这将可能有助于减少 人类疾病的负担。这项研究的结果将是重要的，因为 从这项研究中获得的基本知识有望促进促进健康的方法， living.

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