Interactions between the immune response and lipid homeostasis in regulating sleep during sickness

免疫反应与脂质稳态之间的相互作用在调节疾病期间的睡眠中

• 批准号: 10634707
• 负责人: NIRMALA NIRINJINI NAIDOO
• 金额: $ 48.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634707
• 关键词: Autoimmune; Bacterial Infections; Behavior; Behavioral Genetics; Biochemical; Brain; Cells; Characteristics; Chronic; Chronic Fatigue Syndrome; Data; Disease; Drosophila genus; Drowsiness; Fatigue; Feedback; Genetic Models; Homeostasis; Human; Immune; Immune response; Immune system; Infection; Injury; Innate Immune Response; Innate Immune System; Link; Lipid Bilayers; Lipids; Mammals; Mediating; Metabolic; Nuclear; Pathway interactions; Patients; Production; Proteins; Recovery; Reporting; Signal Transduction; Sleep; Sleep Deprivation; Stress; Testing; XBP1 gene; acute stress; antimicrobial peptide; fly; lipid metabolism; lipidomics; neoplastic; novel; overexpression; pharmacologic; prevent; response; stress reduction; stressor; transcription factor

Project Summary When sick with an infectious, autoimmune, or neoplastic disease, humans report sleepiness and excess or unrefreshing sleep. The features of human sleep during sickness are shared with those in Drosophila. Sickness behavior in fruit flies as in humans and other species is induced by stressors such as bacterial infection or aseptic injury, which reduce activity and increase sleep. While the causal mechanisms underlying altered sleep during sickness are unknown, immune system and lipid dysregulation are implicated. We will exploit the Drosophila genetic model to directly test specific interactions between the innate immune system and lipid homeostasis to determine how these interactions contribute to sleep need during sickness. We recently identified a novel brain-expressed antimicrobial peptide (AMP) nemuri (nur), which links the immune response with sleep. nur is strongly induced by infection and sleep deprivation and loss of it reduces sleep under these conditions. Our preliminary data indicate that induction of nur is mediated by Nuclear Factor κB transcription factors (NFκB). Overexpression of nur in the brain also promotes sleep and is associated with dysregulation of lipid metabolism in a manner that parallels that of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Preliminary data also indicate lipid depletion by sustained sleep deprivation. Based on these findings, we hypothesize that prolonged expression of nemuri, either genetically or as induced by chronic sleep deprivation or infection, causes lipid bilayer stress (LBS). Under normal circumstances, the unfolded protein response, mediated by IRE1/XBP1 signaling, resolves LBS (UPRLBS) and terminates the acute stress-induced sleep response. However, prolonged activation of nur disrupts NFκB activity, which is central to the innate immune response. The suppression of NFκB signaling subsequently prevents an appropriate response to LBS by reducing the adaptive lipid homeostatic UPRLBS, thereby increasing sleep need. We will use behavioral genetic, lipidomic, biochemical, and pharmacological approaches to test key aspects of this hypothesis. Given that immune, lipid metabolic, and UPR pathways are highly conserved between flies and mammals, results of our proposed studies will provide a framework for understanding a mechanism for sleep during sickness, with implications for unrefreshing sleep and fatigue associated with numerous illnesses in humans.

项目概要 当患有传染性、自身免疫性或肿瘤性疾病时，人类会报告嗜睡和过度或 睡眠不清爽。人类生病期间的睡眠特征与果蝇的睡眠特征相同。 与人类和其他物种一样，果蝇的疾病行为是由细菌等应激源引起的 感染或无菌损伤，会减少活动并增加睡眠。虽然潜在的因果机制 生病期间睡眠的改变尚不清楚，这与免疫系统和脂质失调有关。我们将 利用果蝇遗传模型直接测试先天免疫系统之间的特定相互作用 和脂质稳态，以确定这些相互作用如何影响生病期间的睡眠需求。我们 最近发现了一种新型脑表达抗菌肽 (AMP) nemuri (nur)，它将免疫 以睡眠来回应。 nur 是由感染和睡眠剥夺强烈诱发的，缺乏它会减少睡眠 在这些条件下。我们的初步数据表明 nur 的诱导是由核因子 κB 介导的 转录因子（NFκB）。大脑中 nur 的过度表达也能促进睡眠，并与 脂质代谢失调的方式与肌痛患者相似 脑脊髓炎/慢性疲劳综合征（ME/CFS）。初步数据还表明，脂质消耗 持续剥夺睡眠。基于这些发现，我们假设 nemuri 的延长表达， 无论是遗传原因还是慢性睡眠不足或感染引起的，都会导致脂质双层应激 (LBS)。 正常情况下，由 IRE1/XBP1 信号介导的未折叠蛋白反应可解决 LBS （UPRLBS）并终止急性压力引起的睡眠反应。然而，长时间激活nur 破坏 NFκB 活性，这是先天免疫反应的核心。 NFκB信号传导的抑制 随后通过降低适应性脂质稳态 UPRLBS 来阻止对 LBS 的适当反应， 从而增加睡眠需求。我们将使用行为遗传学、脂质组学、生化和药理学 检验该假设关键方面的方法。鉴于免疫、脂质代谢和 UPR 途径 在果蝇和哺乳动物之间高度保守，我们提出的研究结果将为 了解生病期间的睡眠机制，对睡眠不足和疲劳有影响 与人类的多种疾病有关。