Circadian regulation of physiological functions

摘要：我的实验室研究昼夜节律的过程及其对健康和疾病的贡献。 昼夜节律指的是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，昼夜节律是由转录负反馈控制的 循环称为昼夜节律时钟。昼夜节律时钟在表达数百个 几乎每个组织中的基因都被检查并驱动细胞、组织特异性和行为的日常振荡 功能。由于时差或夜班工作导致的昼夜节律慢性紊乱与多个 先天性免疫力、新陈代谢和睡眠方面的缺陷。许多疾病状态也与丧失 昼夜节律，包括细菌感染、代谢性疾病和神经系统疾病。尽管 众所周知，昼夜节律的丧失对人类生理学有深远的影响，知识的一个主要缺口是 识别在特定疾病的发病机制中起作用的昼夜节律调节功能。 在上一个资助期，我们的MIRA支持开发工具来增强或抑制果蝇 生物钟；果蝇和小鼠神经胶质功能的研究；以及一个核心的研究 果蝇的睡眠功能。在目前的提案中，我们关注的是昼夜节律调节的新陈代谢，它有 成为我们工作中的一个主要主题。我们描述了两个涉及昼夜节律代谢的项目 果蝇：慢性短睡眠对氧化应激的敏感性(项目1)与宿主的代谢调节 细菌感染的耐受性(项目2)。 ·项目1：睡眠是昼夜节律最明显的表现之一。睡眠，或必要的休息 在24小时昼夜节律周期中，在进化上是保守的。然而，睡眠的生理功能 目前仍不清楚。我们发表的米拉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，慢性短时睡眠会导致 由于新陈代谢的潜在变化而对氧化应激敏感。我们将在项目1中调查这一点。 ·项目2：有两种防御感染的机制：抵抗和耐受。 耐药机制杀死病原体，而耐受机制限制感染的致病效果。 与抵抗相比，人们对容忍的理解要少得多。在NIGMS资助的研究中，我的实验室之前 确定了一种受昼夜节律调节的、TORC2介导的宿主对洋葱芽孢杆菌感染的耐受机制。 在初步数据中，我们发现Sting突变体也提高了对洋葱芽孢杆菌感染的耐受性。 干扰素基因刺激物(STING)途径是一种保守的先天免疫反应，已知 抗性机制。在哺乳动物和果蝇身上，刺还有第二个不同的功能： 调节脂类代谢。我们将调查刺痛在免疫和新陈代谢中的作用 在项目2中的感染期间相交。

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.