Mechanisms of Cellular Stress-Induced Sleep

细胞压力诱发睡眠的机制

• 批准号: 9175443
• 负责人: NIRMALA NIRINJINI NAIDOO
• 金额: $ 33.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175443
• 关键词: Acute; Address; Aging; Alzheimer' s Disease; Apoptotic; Bacterial Infections; Behavioral Genetics; Binding; Biochemical Genetics; Biological Assay; Brain; Cardiovascular Diseases; Cardiovascular system; Cellular Stress; Cellular Stress Response; Chronic; Chronic stress; Complex; Data; Dependence; Disease; Drosophila genus; Enzymes; Fat Body; Genetic Models; Immune response; Immunoglobulin binding proteins; Immunoglobulins; Infection; Inflammation; Inflammatory; Injury; Inositol; Life; Link; Luciferases; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Chaperones; Monitor; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Organism; Parkinson Disease; Pathway interactions; Phosphotransferases; Process; Proteins; Publishing; Recovery; Reporter; Ribonucleases; Signal Pathway; Signal Transduction; Site; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Specificity; Staging; Stress; Testing; Time; Tissues; Up-Regulation; Western Blotting; Work; acute stress; age related; base; behavioral response; endoplasmic reticulum stress; fly; genetic approach; human disease; overexpression; protein function; response; Acute; Address; Aging; Alzheimer' s Disease; Apoptotic; Bacterial Infections; Behavioral Genetics; Binding; Biochemical Genetics; Biological Assay; Brain; Cardiovascular Diseases; Cardiovascular system; Cellular Stress; Cellular Stress Response; Chronic; Chronic stress; Complex; Data; Dependence; Disease; Drosophila genus; Enzymes; Fat Body; Genetic Models; Immune response; Immunoglobulin binding proteins; Immunoglobulins; Infection; Inflammation; Inflammatory; Injury; Inositol; Life; Link; Luciferases; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Chaperones; Monitor; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Organism; Parkinson Disease; Pathway interactions; Phosphotransferases; Process; Proteins; Publishing; Recovery; Reporter; Ribonucleases; Signal Pathway; Signal Transduction; Site; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Specificity; Staging; Stress; Testing; Time; Tissues; Up-Regulation; Western Blotting; Work; acute stress; age related; base; behavioral response; endoplasmic reticulum stress; fly; genetic approach; human disease; overexpression; protein function; response

Project Summary This proposal addresses a mechanism by which cellular stress influences sleep. Our working hypothesis is that acute stress that occurs with short-term sleep loss or during an early stage of infection causes cellular stress that leads to an acute restorative sleep response. However, during prolonged chronic stress, the acute sleep response dissipates and sleep becomes fragmented. Sleep also disintegrates and becomes fragmented with aging and a number of human diseases, including cardiovascular, metabolic and neurodegenerative disorders including Alzheimer's disease, all of which involve an inflammatory process. However, the cellular and molecular mechanisms by which this occurs remains poorly understood. Our recent findings indicate that endoplasmic reticulum (ER) stress contributes to sleep fragmentation. The unfolded protein response (UPR), which alleviates ER stress, also alleviates fragmented sleep. However, the mechanisms by which ER stress disrupts sleep and the UPR promotes sleep are unclear. In an effort to understand how the UPR promotes restorative sleep, this proposal exploits the Drosophila model to address questions regarding the complex relationship between inflammation, ER stress, the UPR, and sleep. Drosophila and other organisms show a transient increase in sleep in response to stress, including infection, aseptic injury, and sleep deprivation. The recent observation that extending stress-induced sleep prolongs survival during infection indicates that this is an important and adaptive behavioral response. Based on published and preliminary studies, we hypothesize that the UPR and ER stress modulate sleep via a Jun-N-terminal kinase (JNK) dependent signaling pathway. We will use biochemical and behavioral genetic approaches to test key components of this hypothesis in both sleep deprivation and infection assays. Results of these studies will reveal a mechanism for restorative sleep and for how sleep disintegrates with chronic inflammation. Findings from this project will have important implications for treatment of sleep disturbances as prodromal markers of neurodegenerative and other age- related diseases such as Parkinson's and Alzheimer's disease.

项目摘要 该提案解决了细胞应力影响睡眠的机制。我们工作的假设是 短期睡眠丧失或感染早期会导致细胞应激发生的急性应激 这导致急性恢复性睡眠反应。但是，在长时间的慢性压力期间，急性睡眠 反应消散，睡眠变得分散。睡眠也会分解并因 衰老和许多人类疾病，包括心血管，代谢和神经退行性疾病 包括阿尔茨海默氏病，所有这些都涉及炎症过程。但是，细胞和 发生这种情况的分子机制仍然很少理解。我们最近的发现表明 内质网（ER）应力有助于睡眠破裂。展开的蛋白质反应（UPR）， 减轻了ER压力，还减轻了零散的睡眠。但是，ER应力的机制 干扰睡眠，UPR促进睡眠尚不清楚。为了了解UPR如何促进 恢复性睡眠，该提案利用果蝇模型解决有关该综合体的问题 炎症，ER压力，UPR和睡眠之间的关系。果蝇和其他生物显示 暂时对压力的睡眠增加，包括感染，无菌损伤和睡眠剥夺。这 最近的观察结果，即延伸压力引起的睡眠会延长感染期间的生存率，这表明这是 一个重要的自适应行为反应。根据已发表和初步研究，我们假设 UPR和ER应力通过依赖性信号通路通过Jun-N-N末端激酶（JNK）调节睡眠。 我们将使用生化和行为遗传方法来检验这两个假设的关键组成部分 睡眠剥夺和感染分析。这些研究的结果将揭示恢复性睡眠的机制 以及睡眠如何与慢性炎症分解。该项目的发现将具有重要的 对治疗睡眠障碍的影响是神经退行性和其他年龄的前驱标记 相关疾病，例如帕金森氏病和阿尔茨海默氏病。