Integrated stress response and the circadian clock

项目摘要 这项建议的总体目标是阐明整合应激之间的特定串扰机制 反应(ISR)和昼夜节律计时是神经元中的两个基本生物学过程。昼夜节律 调节神经元的分化、可塑性和组织再生，其破坏有助于多种 人类健康问题。生物钟基因在几乎所有细胞中都广泛表达。要正常运行， 细胞时钟必须与细胞生理和新陈代谢相结合和同步。ISR是一种保守的 细胞内信号网络，使细胞对应激源做出反应并恢复内稳态。然而，人们对此知之甚少， 关于ISR是否以及如何与生物钟整合，这构成了我们对 神经元的动态平衡整合。我们最近发表的工作表明，ISR可能是一种保守的 将细胞应激反应与昼夜计时相结合的机制。基于已发表的作品和 未发表的初步数据，在这里，我们建议检验ISR与 哺乳动物生物钟：ISR调节基本的时钟特性，包括夹带和 昼夜节律，而时钟根据一天中的时间控制ISR响应。我们将利用我们的 专业知识和独特的小鼠模型，使用分子、细胞和 行为方法。目标1将定义ISR抑制剂IMPACT(印迹和古老基因蛋白)的作用 在调节昼夜节律时钟的光携带方面。目标2将确定未折叠蛋白反应的作用 和PERK(蛋白激酶R样内质网状激酶)在昼夜计时中的作用。目标3将阐明 EIF2(真核翻译起始因子2)在昼夜节律中依赖的翻译调控机制 钟。这项拟议的工作具有创新性，因为它利用了新的老鼠基因工具来解决概念上的问题 关于ISR和时钟之间的串扰机制的新问题。这些捐款是意料之中的 意义重大，因为预计它将揭示两者之间的机械联系，这一点至关重要 细胞过程。重要的是，在复杂的大脑疾病中，ISR经常出错，这通常与 由于未知的机制，患者的日常节律被打乱。因为ISR可以成为FDA批准的目标 药物，了解它在昼夜生理学中的作用可能会为调节生物钟提供新的机会 用于治疗这些疾病中的时钟功能障碍。

Project Summary The overall objective of this proposal is to elucidate specific crosstalk mechanisms between the integrated stress response (ISR) and circadian timekeeping, two fundamental biological processes in neurons. Circadian rhythm regulates neuronal differentiation, plasticity, and tissue regeneration and its disruption contributes to a variety of human health problems. Circadian clock genes are widely expressed in almost all cells. To function properly, the cellular clock must integrate and synchronize with cellular physiology and metabolism. ISR is a conserved intracellular signaling network for cells to respond to stressors and restore homeostasis. Little is known, however, on whether and how ISR integrates with the circadian clock, which forms a major gap in our understanding of homeostatic integration in neurons. Our recently published work indicates that ISR may be a conserved mechanism that couples cellular stress response to circadian timekeeping. Based on the published work and unpublished preliminary data, here we propose to test the overall hypothesis that ISR interacts with the mammalian circadian clock: ISR regulates fundamental clock properties including entrainment and circadian period, whereas the clock controls ISR response based on the time of day. We will leverage our expertise and unique mouse models to test the hypothesis using a combination of molecular, cellular, and behavioral approaches. Aim 1 will define a role for the ISR inhibitor IMPACT (imprinted and ancient gene protein) in regulating photic entrainment of the circadian clock. Aim 2 will identify a role for unfolded protein response and PERK (protein kinase R-like endoplasmic reticulum kinase) in circadian timekeeping. Aim 3 will elucidate eIF2 (eukaryotic translation initiation factor 2)-dependent translational control mechanisms in the circadian clock. The proposed work is innovative, because it utilizes new mouse genetic tools to address conceptually novel questions regarding the crosstalk mechanisms between ISR and the clock. The contributions are expected to be significant, because it is expected to uncover mechanistic links between the two fundamentally important cellular processes. Importantly, ISR frequently goes awry in complex brain disorders, which are often associated with disrupted daily rhythms in patients due to unknown mechanisms. As ISR can be targeted by FDA-approved drugs, understanding its role in circadian physiology may offer new opportunities to regulate the body clock function and to treat clock dysfunctions in these diseases.