Mechanisms of Cellular Stress-Induced Sleep

项目摘要 这项提议提出了细胞压力影响睡眠的机制。我们的假设是 短期睡眠不足或感染早期出现的急性应激会导致细胞应激 导致急性恢复性睡眠反应。然而，在长期的慢性压力下，急性睡眠 反应消失，睡眠变得支离破碎。睡眠也会分解，变得支离破碎， 衰老和许多人类疾病，包括心血管、代谢和神经退行性疾病 包括老年痴呆症，所有这些都涉及炎症过程。然而，细胞和 其发生的分子机制仍然知之甚少。我们最近的发现表明， 内质网（ER）应激导致睡眠片段化。未折叠蛋白反应（UPR）， 这会增加急诊室的压力，也会增加睡眠的碎片。然而，内质网应激的机制 干扰睡眠和促进睡眠的普遍定期审议尚不清楚。为了了解普遍定期审议如何促进 恢复性睡眠，这项建议利用果蝇模型来解决有关复杂的问题， 炎症、ER应激、UPR和睡眠之间的关系。果蝇和其他生物显示出 对压力的反应是短暂的睡眠增加，包括感染、无菌性损伤和睡眠剥夺。的 最近的观察表明，在感染期间，延长压力诱导的睡眠会降低生存率，这表明， 一种重要的适应性行为反应基于已发表的和初步的研究，我们假设 UPR和ER应激通过Jun-N-末端激酶（JNK）依赖的信号通路调节睡眠。 我们将使用生物化学和行为遗传学的方法来测试这一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 以及睡眠如何随着慢性炎症而分解。该项目的结果将具有重要意义 作为神经退行性疾病和其他年龄的前驱标志物的睡眠障碍治疗的意义- 相关疾病，如帕金森氏症和阿尔茨海默氏症。

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.