Identifying the role of the ocular immune response in age-related sleep disturbances

确定眼部免疫反应在与年龄相关的睡眠障碍中的作用

基本信息

项目摘要

Project Summary Sleep is a conserved function across evolution that is critical for maintaining health and promoting longevity. With age, there are declines in sleep quality that often precede, and are associated with, the onset of disease. However, the mechanisms responsible for sleep senescence are unclear. In both humans and the fruit fly, Drosophila melanogaster, endogenous circadian clocks that set 24h rhythms in sleep and activity are influenced by light input received from the eye. However, with age, there are declines in vision and a dampening of circadian rhythms. Concomitant with this decline, is a chronic activation of the immune system. A central regulator of the immune response is the transcription factor Nuclear Factor Kappa-B (NF-κB), which in both flies and mammals coordinates the response to bacterial pathogens and damage signals. Using a bioinformatics approach in Drosophila, we identified that genes regulated by NF-κB show elevated expression in the photoreceptor cells with age. With this observation in mind, we tested the hypothesis that changes that occur in the eye with age drive sleep senescence. We found that inhibiting the NF-κB homolog, relish, in the photoreceptor cells maintains total sleep time and sleep consolidation with age, suggesting that increases in the ocular immune response drives sleep senescence. Furthermore, we have identified that housing flies in constant darkness suppresses the expression of NF-κB-regulated genes in the fly head, indicating that NF-κB activity is regulated by light. This proposal builds on these preliminary findings with two specific aims. In Aim#1, we will identify genes that are regulated by NF-κB in the eye and that drive sleep senescence. To accomplish this, we have compiled a list of genes whose expression is significantly changed in the photoreceptors with age, and with loss of relish. We will inhibit each of these candidate genes in the photoreceptors and identify genes whose loss-of-function sleep phenotype mimics the effect of relish. In Aim #2, we will firmly establish whether light and the phototransduction signaling cascade promotes NF-κB activity in the photoreceptors. For this, we will use an existing luciferase-based genetic reporter for NF-κB that we can express in the photoreceptor cells. Using the powerful genetic tools available to Drosophila, we will be able to test whether genes involved in the phototransduction signaling cascade affect NF-κB luciferase reporter activity, allowing us to pinpoint the mechanism through which light regulates NF-κB. Ultimately, this work will reveal the mechanism through which eye aging affects sleep senescence, and will identify conserved genetic targets that may be modulated in mammals for preserving sleep quality with age.
项目概要 睡眠是整个进化过程中的保守功能,对于维持健康和延长寿命至关重要。 随着年龄的增长,睡眠质量会下降,这通常先于疾病的发生,并与疾病的发生相关。 然而,导致睡眠衰老的机制尚不清楚。在人类和果蝇中, 果蝇,内源性生物钟,设定 24 小时睡眠和活动节律 受从眼睛接收到的光输入的影响。但随着年龄的增长,视力会下降, 昼夜节律的抑制。与这种衰退相伴的是免疫系统的慢性激活。一个 免疫反应的中枢调节因子是转录因子核因子 Kappa-B (NF-κB),它在 果蝇和哺乳动物都协调对细菌病原体和损伤信号的反应。使用 通过生物信息学方法在果蝇中,我们发现受 NF-κB 调节的基因表现出升高的表达 感光细胞随着年龄的增长。考虑到这一观察,我们测试了改变这一假设的假设 随着年龄的增长,眼睛会出现睡眠衰老现象。我们发现抑制 NF-κB 同源物,津津有味, 随着年龄的增长,感光细胞维持总睡眠时间和睡眠巩固,这表明感光细胞的增加 眼部免疫反应导致睡眠衰老。此外,我们发现住房飞速增长 持续黑暗抑制果蝇头部 NF-κB 调节基因的表达,表明 NF-κB 活动受光调节。该提案建立在这些初步调查结果的基础上,有两个具体目标。在目标#1中, 我们将鉴定眼睛中受 NF-κB 调节并驱动睡眠衰老的基因。为了完成 为此,我们编制了一份基因列表,这些基因的表达在光感受器中发生显着变化 年纪大了,也失去了兴趣。我们将抑制光感受器中的每个候选基因并识别 其功能丧失的睡眠表型模仿津津有味的影响的基因。在目标#2中,我们将坚定地建立 光和光转导信号级联是否促进光感受器中的 NF-κB 活性。为了 为此,我们将使用现有的基于荧光素酶的 NF-κB 基因报告基因,我们可以在 感光细胞。利用果蝇可用的强大遗传工具,我们将能够测试是否 参与光转导信号级联的基因影响 NF-κB 荧光素酶报告基因活性,使我们能够 查明光调节 NF-κB 的机制。最终,这项工作将揭示其机制 通过眼睛老化影响睡眠衰老,并将识别可能的保守遗传目标 在哺乳动物中进行调节,以随着年龄的增长保持睡眠质量。

项目成果

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Geoffrey Meyerhof其他文献

Geoffrey Meyerhof的其他文献

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{{ truncateString('Geoffrey Meyerhof', 18)}}的其他基金

Identifying the role of the ocular immune response in age-related sleep disturbances
确定眼部免疫反应在与年龄相关的睡眠障碍中的作用
  • 批准号:
    10669766
  • 财政年份:
    2021
  • 资助金额:
    $ 3.94万
  • 项目类别:
Identifying the role of the ocular immune response in age-related sleep disturbances
确定眼部免疫反应在与年龄相关的睡眠障碍中的作用
  • 批准号:
    10312603
  • 财政年份:
    2021
  • 资助金额:
    $ 3.94万
  • 项目类别:

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