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（由适用提供）：最近的研究表明，患病患者的睡眠不佳，经常干扰，昼夜节律丧失以及在恢复阶段所花费的时间的百分比明显减少。重要的是，这些患者的睡眠剥夺可能会带来不利的后果。为了与这个概念保持一致，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，但是造成这种现象的机制是完全未知的。我们将测试特定的假设，即睡眠剥夺与感染相互作用以激活内质网应激途径，而ER应力途径激活又导致多个器官的失败。 AIM 1将确定感染和睡眠剥夺是否在多次中协同诱导ER应力，以及ER应力途径激活是否会导致器官衰竭。研究将使用败血症的动物模型（Cecal结扎和穿刺，CLP）和睡眠剥夺（SD）进行。实验1.1将检验以下假设：败血症和睡眠剥夺相互作用以诱导ER应激，而ER应力途径与器官衰竭的发展并行激活。实验1.2将检验以下假设：ER应激的化学激活会触发导致器官功能障碍的病理改变（例如，下游蛋白水解途径的激活）。 AIM 2将阐明败血症和睡眠剥夺激活ER应力途径的上游机制。实验2.1将检验以下假设：细胞因子诱导的活性氧（ROS）是激活脓毒症中的ER应力的关键上游触发。实验2.2将检验以下假设：外周组织时钟基因功能的上游改变会激活ER应力途径，以响应睡眠剥夺。实验2.3将检验以下假设：外周组织时钟功能的破坏会增加ROS的产生，并激活ER应力途径。 AIM 3将确定ER应力途径的药理学抑制剂是否可以改善败血症和睡眠剥夺中器官的功能。实验3.1、3.2和3.3将检验以下假设。 ATAD-FMK（caspase 12抑制剂），salubrinal（EIF2¿去磷酸化的选择性抑制剂）或褪黑激素（抑制IRE1途径的内源性恐怖）将阻止ER应力途径依赖性ER应力途径依赖性细胞和CLP+SD中的器官功能。实验3.4将检验以下假设：延迟给药以产生最佳治疗作用的药理剂将阻止ER应力途径依赖性细胞损伤并改善CLP+SD中器官功能。