Circadian regulation of physiological functions

生理功能的昼夜调节

• 批准号: 10623711
• 负责人: Michele M Shirasu-Hiza
• 金额: $ 44.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623711
• 关键词: Bacteria; Bacterial Infections; Behavioral; Biological Process; Burkholderia cepacia; Chronic; Circadian Dysregulation; Circadian Rhythms; Data; Defect; Defense Mechanisms; Disease; Disease Progression; Drosophila genus; Feedback; Funding; Genes; Genetic Transcription; Health; Hour; Human; Immunity; Infection; Innate Immune Response; Investigation; Jet Lag Syndrome; Knowledge; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; National Institute of General Medical Sciences; Natural Immunity; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Physiological; Physiology; Process; Publishing; Regulation; Research; Resistance; Rest; Role; Sleep; Stimulator of Interferon Genes; Sting Injury; Tissues; Work; circadian; circadian pacemaker; circadian regulation; lipid metabolism; mutant; nervous system disorder; pathogen; resistance mechanism; shift work; tool development

SUMMARY: My lab studies circadian-regulated processes and their contributions to health and disease. Circadian regulation refers to daily oscillations in biological functions and is an evolutionarily conserved feature from bacteria to humans. At its core, circadian regulation is governed by a transcriptional negative feedback loop called the circadian clock. Circadian clocks generate 24-hour oscillations in the expression of hundreds of genes in almost every tissue examined and drive the daily oscillation of cellular, tissue-specific, and behavioral functions. Chronic disruption of circadian regulation due to jetlag or night-shift work is associated with multiple defects in innate immunity, metabolism, and sleep. Many disease states are also associated with loss of circadian regulation, including bacterial infection, metabolic diseases, and neurological diseases. Despite the known profound effects of loss of circadian regulation on human physiology, a major gap in knowledge is the identification of circadian-regulated functions that contribute to the pathogenesis of specific diseases. In the last funding period, our MIRA supported the development of tools to enhance or inhibit Drosophila circadian clocks; the investigation of glial function in both Drosophila and mice; and the investigation of a core function for sleep in Drosophila. In the current proposal, we focus on circadian-regulated metabolism, which has emerged as a major theme in our work. We describe two projects involving circadian-regulated metabolism in Drosophila: sensitivity to oxidative stress due to chronic short sleep (Project 1) and metabolic regulation of host tolerance of bacterial infection (Project 2). · Project 1: One of the most obvious manifestations of circadian rhythm is sleep. Sleep, or obligate rest during the 24-hour circadian cycle, is evolutionarily conserved. Yet the physiological function of sleep remains unclear. Our published MIRA-funded results support the hypothesis that a key function of sleep is defense against oxidative stress. Our more recent preliminary data suggest that chronic short sleep causes sensitivity to oxidative stress due to underlying changes in metabolism. We will investigate this in Project 1. · Project 2: There are two types of defense mechanisms against infection: resistance and tolerance. Resistance mechanisms kill pathogens, while tolerance mechanisms limit the pathogenic effects of infection. Tolerance is much less well understood than resistance. In NIGMS-funded research, my lab previously identified a circadian-regulated, TORC2-mediated mechanism of host tolerance against B. cepacia infection. In preliminary data, we found that Sting mutants also have increased tolerance against B. cepacia infection. The Stimulator of Interferon Genes (STING) pathway is a conserved innate immune response and known resistance mechanism. STING also has a second distinct function in both mammals and Drosophila: regulation of lipid metabolism. We will investigate whether STING’s roles in immunity and metabolism intersect during infection in Project 2.

我的实验室研究昼夜节律调节过程及其对健康和疾病的贡献。 昼夜节律调节是指生物功能的每日振荡，是进化上保守的特征 从细菌到人类。在其核心，昼夜节律调节是由一个转录负反馈 称为生物钟的循环。生物钟产生24小时的振荡，表达数百种 几乎每一个组织中的基因检查和驱动细胞，组织特异性和行为的日常振荡 功能协调发展的由于时差或夜班工作造成的昼夜节律调节的慢性中断与多种 先天免疫、新陈代谢和睡眠缺陷。许多疾病状态也与丧失 昼夜节律调节，包括细菌感染、代谢性疾病和神经系统疾病。尽管 已知昼夜节律调节的丧失对人类生理的深远影响，知识上的一个主要空白是 识别有助于特定疾病发病机制的昼夜节律调节功能。 在上一个资助期内，我们的MIRA支持了增强或抑制果蝇的工具的开发 生物钟;果蝇和小鼠神经胶质功能的研究;以及核心神经元的研究。 果蝇的睡眠功能。在目前的建议中，我们专注于昼夜节律调节的新陈代谢， 成为我们工作中的一个重要主题。我们描述了两个项目，涉及昼夜节律调节代谢， 果蝇对慢性短睡眠引起的氧化应激的敏感性（项目1）和宿主的代谢调节 细菌感染的耐受性（项目2）。 项目1：昼夜节律最明显的表现之一就是睡眠。睡眠或强制性休息 在24小时的生理周期中，是进化保守的。然而睡眠的生理功能 仍不清楚我们发表的MIRA资助的结果支持了睡眠的一个关键功能是 防御氧化应激。我们最近的初步数据表明，长期睡眠不足会导致 由于代谢的潜在变化而对氧化应激敏感。我们将在项目1中对此进行研究。 ·项目2：有两种类型的防御机制对抗感染：抵抗和耐受。 抗性机制杀死病原体，而耐受机制限制感染的致病作用。 宽容远不如抵制那么容易理解。在NIGMS资助的研究中，我的实验室以前 确定了昼夜节律调节、TORC 2介导的宿主对B的耐受机制。洋葱感染 在初步数据中，我们发现Sting突变体也具有增加的对B的耐受性。洋葱感染 干扰素基因刺激物（STING）途径是保守的先天免疫应答，并且已知是一种免疫应答。 抗性机制STING在哺乳动物和果蝇中也有第二个不同的功能： 调节脂质代谢。我们将研究STING在免疫和代谢中的作用 在项目2的感染过程中相交