Integrated stress response and the circadian clock

综合压力反应和生物钟

• 批准号: 10915228
• 负责人: Ruifeng (Ray) Cao
• 金额: $ 32.97万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10915228
• 关键词: Address; Animals; Behavioral; Behavioral Assay; Binding; Biological Clocks; Biological Process; Bioluminescence; Brain Diseases; Cell physiology; Cells; Cellular Metabolic Process; Cellular Stress; Circadian Rhythms; Complex; Coupled; Couples; Data; Disease; Dissociation; Endoplasmic Reticulum; Eukaryotic Initiation Factors; Exhibits; FDA approved; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic; Health; Health Promotion; Homeostasis; Homologous Gene; Human; Human body; Knockout Mice; Knowledge; Light; Link; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; Neuronal Differentiation; Neurons; Neurospora; Organism; Pathway interactions; Patients; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Phosphotransferases; Physiology; Prokaryotic Initiation Factor-2; Property; Proteins; Publishing; Regulation; Reporting; Research; Role; Running; Signal Transduction; Slice; Speed; Stress; Testing; Time; Transcript; Work; biological adaptation to stress; biological systems; circadian; circadian pacemaker; circadian regulation; conditional mutant; efficacy evaluation; human disease; imprint; improved; inhibitor; innovation; loss of function; mRNA Translation; mouse genetics; mouse model; novel; pharmacologic; physiologic stressor; polysome profiling; protein kinase R; protein misfolding; response; stressor; tissue regeneration; tool; transcriptome sequencing; translatome

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.

项目概要 该提案的总体目标是阐明综合应力之间的具体串扰机制 反应（ISR）和昼夜节律计时，神经元中的两个基本生物过程。昼夜节律 调节神经元分化、可塑性和组织再生，其破坏导致多种 人类健康问题。生物钟基因在几乎所有细胞中广泛表达。为了正常运行， 细胞时钟必须与细胞生理和新陈代谢整合并同步。 ISR 是一个保守的 细胞内信号网络，用于细胞响应应激并恢复体内平衡。然而鲜为人知的是， 关于 ISR 是否以及如何与生物钟整合，这在我们的理解中形成了一个重大差距 神经元内的稳态整合。我们最近发表的工作表明 ISR 可能是一个保守的 将细胞应激反应与昼夜节律结合起来的机制。根据已发表的作品和 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 调节基本时钟特性，包括夹带和 昼夜节律周期，而时钟则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，结合分子、细胞和技术来检验假设 行为方法。目标 1 将定义 ISR 抑制剂 IMPACT（印记和古老基因蛋白）的作用 调节生物钟的光夹带。目标 2 将确定未折叠蛋白反应的作用 和 PERK（蛋白激酶 R 样内质网激酶）在昼夜节律计时中的作用。目标 3 将阐明 昼夜节律中 eIF2（真核翻译起始因子 2）依赖性翻译控制机制 钟。拟议的工作具有创新性，因为它利用新的小鼠遗传工具从概念上解决了 关于 ISR 和时钟之间的串扰机制的新问题。预计捐款 意义重大，因为它有望揭示两者之间根本上重要的机械联系 细胞过程。重要的是，ISR 在复杂的脑部疾病中经常出错，这些疾病通常与 由于未知的机制，患者的日常节律被打乱。由于 ISR 可以被 FDA 批准作为目标 药物，了解其在昼夜节律生理学中的作用可能会为调节生物钟提供新的机会 功能并治疗这些疾病中的时钟功能障碍。