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.

项目摘要 该提案的总体目的是阐明综合应力之间的特定串扰机制 反应（ISR）和昼夜节律，这是神经元中的两个基本生物学过程。昼夜节律 调节神经元分化，可塑性和组织再生及其破坏有助于多种 人类健康问题。昼夜节律基因在几乎所有细胞中都广泛表达。为了正常运作， 细胞时钟必须与细胞生理学和代谢进行整合并同步。 ISR是保守的 细胞内信号网络响应压力源并恢复体内平衡。然而，鲜为人知 关于ISR是否以及如何与昼夜节律集成在一起，这在我们的理解中构成了一个主要差距 神经元中的稳态整合。我们最近发表的工作表明ISR可能是保守的 将细胞应力反应伴随着昼夜节律的机制。根据已发表的工作和 未发表的初步数据，我们在这里提议测试ISR与此相互作用的总体假设 哺乳动物昼夜节律时钟：ISR调节基本时钟属性，包括夹带和 昼夜节律时期，而时钟则基于一天中的时间来控制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。 AIM 1将定义ISR抑制剂影响的作用（印迹和古代基因蛋白） 在调节昼夜节律的光学夹带时。 AIM 2将确定展开蛋白质反应的作用 和PERK（蛋白激酶R样的内质网激酶）和昼夜节时间。 AIM 3将阐明 EIF2（真核翻译起始因子2）二生纪的依赖性翻译控制机制 钟。拟议的工作具有创新性，因为它利用新的鼠标遗传工具在概念上解决 关于ISR与时钟之间的串扰机制的新颖问题。预计捐款 重要的是，因为预计这两个根本重要 细胞过程。重要的是，ISR经常在复杂的脑部疾病中出现问题，这些脑部常常与之相关 由于未知机制，患者的每日节奏破坏了。因为ISR可以通过FDA批准 药物，了解其在昼夜节律生理学中的作用可能会提供调节身体时钟的新机会 功能并治疗这些疾病中的时钟功能障碍。