Effects of Sleep Deprivation on Infection Induced Organ Failure

睡眠不足对感染引起的器官衰竭的影响

基本信息

批准号：
8438584
负责人：
LEIGH A CALLAHAN
金额：
$ 37.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438584
关键词：
Animal Model Animals Area Cause of Death Cells Cessation of life Chemicals Circadian Rhythms Cognitive Complex Critical Illness Data Development Diagnostic tests Disease Functional disorder Generations Genes Goals Heart Diseases Hormones Hospitalization Infection Ligation Light Malignant Neoplasms Melatonin Modeling Multiple Organ Failure Noise Organ Organ failure Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Population Production Protein Dephosphorylation Puncture procedure Reactive Oxygen Species Recovery Risk Sepsis Sleep Sleep Deprivation Staging Survivors Testing Therapeutic Effect Time Tissues United States adverse outcome caspase 12 cell injury cytokine endoplasmic reticulum stress experience gene function improved inhibitor/antagonist mortality novel therapeutics nursing intervention psychologic public health relevance research study response septic

项目摘要

DESCRIPTION (provided by applicant): Recent studies indicate that critically ill patients experience poor sleep, frequent disruptions, loss of circadian rhythm and a marked reduction of the percentage of sleep time spent in restorative stages. Importantly, sleep deprivation in these patients may have adverse consequences. In keeping with this concept, two recent animal studies found that sleep deprivation markedly increases death in sepsis, but the mechanisms responsible for this phenomenon are completely unknown. We will test the specific hypotheses that sleep deprivation interacts with infection to activate endoplasmic reticulum (ER) stress pathways and that ER stress pathway activation, in turn, causes failure of multiple organs. Aim 1 will determine if infection and sleep deprivation synergistically induce ER stress in multiple tissues and if ER stress pathway activation produces organ failure. Studies will be performed using animal models of sepsis (cecal ligation and puncture, CLP) and sleep deprivation (SD). Experiment 1.1 will test the hypothesis that sepsis and sleep deprivation interact to induce ER stress, with ER stress pathways activated in parallel with development of organ failure. Experiment 1.2 will test the hypothesis that chemical activation of ER stress triggers pathological alterations (e.g. activation of downstream proteolytic pathways) that produce organ dysfunction. Aim 2 will elucidate the upstream mechanisms by which sepsis and sleep deprivation activate ER stress pathways. Experiment 2.1 will test the hypothesis that cytokine-induced production of reactive oxygen species (ROS) is the key upstream trigger that activates ER stress in sepsis. Experiment 2.2 will test the hypothesis that upstream alterations in peripheral tissue clock gene function activate ER stress pathways in response to sleep deprivation. Experiment 2.3 will test the hypothesis that disruption of peripheral tissue clock function increases ROS generation, and activates ER stress pathways. Aim 3 will determine if administration of pharmacological inhibitors of ER stress pathways improves organ function in sepsis and sleep deprivation. Experiments 3.1, 3.2, and 3.3 will test the hypothesis that either z- ATAD-fmk (a caspase 12 inhibitor), salubrinal (a selective inhibitor of eIF2¿ dephosphorylation), or melatonin (an endogenous hormone that inhibits the IRE1¿ pathway) will block ER stress pathway dependent cell damage and improve organ function in CLP+SD. Experiment 3.4 will test the hypothesis that delayed administration of the pharmacologic agent to found to produce the best therapeutic effect will block ER stress pathway dependent cell damage and improve organ function in CLP+SD.

描述（由申请人提供）：最近的研究表明，危重患者的睡眠质量不佳、经常受到干扰、昼夜节律丧失以及恢复阶段的睡眠时间百分比显着减少。重要的是，睡眠不足可能会对这些患者产生不利影响。与这一概念相一致的是，最近的两项动物研究发现，睡眠剥夺显着增加了败血症的死亡率，但造成这种现象的机制完全未知，我们将测试睡眠剥夺与感染相互作用的具体假设。激活内质网（ER）应激通路，并且 ER 应激通路激活反过来会导致多个器官衰竭。目标 1 将确定感染和睡眠剥夺是否协同诱导多个组织中的 ER 应激，以及 ER 应激通路激活是否会导致器官衰竭。将使用脓毒症（盲肠结扎和穿刺，CLP）和睡眠剥夺（SD）动物模型进行研究，实验 1.1 将检验脓毒症和睡眠剥夺相互作用诱发的假设。内质网应激，内质网应激激活途径与器官衰竭的发生同时进行，实验 1.2 将检验内质网应激的化学激活引发病理改变（例如下游蛋白水解途径的激活）的假设，目标 2 将阐明上游蛋白水解途径。脓毒症和睡眠剥夺激活 ER 应激途径的机制实验 2.1 将检验细胞因子诱导的活性氧 (ROS) 产生是激活 ER 应激途径的关键上游触发因素的假设。脓毒症中的 ER 应激实验 2.2 将检验外周组织时钟基因功能的上游变化响应睡眠剥夺而激活 ER 应激通路的假设，实验 2.3 将检验外周组织时钟功能的破坏增加 ROS 生成并激活 ER 的假设。目标 3 将确定 ER 应激途径的药物抑制剂是否会改善脓毒症和睡眠剥夺中的器官功能。检验 z- ATAD-fmk（一种 caspase 12 抑制剂）、salubrinal（一种 eIF2¿ 去磷酸化的选择性抑制剂）或褪黑激素（一种抑制 IRE1¿ 通路的内源性激素）将阻断 ER 应激通路依赖性细胞损伤并改善 CLP+SD 中的器官功能实验 3.4 将检验以下假设：延迟施用药物以产生最佳治疗效果将阻断 ER 应激途径依赖性细胞损伤并改善器官功能。中电+标清。