Regulation of sleep-like behavior in C. elegans

秀丽隐杆线虫类睡眠行为的调节

• 批准号: 8013506
• 负责人: David Menassah Raizen
• 金额: $ 33.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013506
• 关键词: Ablation; Address; Afferent Neurons; Animal Model; Animals; Behavior; Behavioral; Biological Models; Caenorhabditis elegans; Chemicals; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Defect; Diagnosis; Epidermal Growth Factor; Figs - dietary; Gene Order; Genes; Genetic; Genetic Models; Genetic Programming; Genetic Screening; Goals; Grant; Growth; Health; Homeostasis; Homologous Gene; Lasers; Life Cycle Stages; Light; Lobular Neoplasia; Modeling; Molecular; Molting; Mutagenesis; Mutation; Nervous system structure; Neurons; Octanols; Patients; Phase; Phenotype; Phylogenetic Analysis; Property; Public Health; Regulation; Research; Response Latencies; Rest; Sensory; Signal Pathway; Signal Transduction; Site; Sleep; Sleep Deprivation; Sleep Disorders; Staging; Stream; System; Testing; Time; Transgenic Organisms; Wakefulness; gain of function; genetic analysis; improved; mutant; operation; phosphoric diester hydrolase; research study; response; sensory gating; sleep onset; sleep regulation

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the genetic regulation of sleep and sleep-like states. Sleep-wake regulation consists of clock timing and of sleep onset and offset signals. Execution of the sleep state requires sensory gating, which refers to the phenomenon of reduced responsiveness during sleep. Sensory gating is a poorly-understood yet fundamental property of sleep that distinguishes it from quiet wakefulness. This proposal aims to advance our mechanistic understanding of sensory gating using the model organism Caenorhabditis elegans. The approach is to study lethargus, a sleep-like period that occurs during the life cycle of C. elegans. In this grant period, the global hypothesis to be tested is that EGL-4/PKG and cAMP signaling act antagonistically in sensory neurons to regulate sensory input during lethargus, and that reduced sensory input in turn facilitates sleep-like behavior. This global hypothesis will be tested through four specific aims. Specific aim 1 will test the hypothesis that the molecular mechanism that regulates sensory responsiveness during lethargus is the same molecular mechanism that regulates chemosensory adaptation. This hypothesis will be tested by assessing for an association between defects in sensory adaptation and defects in sensory gating during lethargus. Additionally, we will test whether animals adapt more readily during lethargus than outside of lethargus. Specific aim 2 will test the hypothesis that cAMP signaling acts in sensory neurons to antagonize sensory gating during lethargus. This hypothesis will be tested by expressing the gene pde-4, which normally degrades cAMP, in sensory neurons. In addition, we will assess the gene order relationship between egl-4 and pde-4 is regulating sensory gating. Specific aim 3 will test the hypothesis that sensory input regulates sleep-like behavior. This third aim will be tested by examining the effects on sleep-like behavior of dampening sensory input during lethargus and of mutants and operations that reduce sensory function. The final specific aim will perform a genetic screen to identify genes required for the enhanced sleep- like behavior in egl-4 gain of function mutants. Given the phylogenetic conservation of sleep and sleep-like states and the conservation of cGMP-and cAMP-dependent signaling pathways, it is likely that these experiments will shed light on sleep regulation in other species. Improved understanding of sleep regulation will enhance the diagnosis and treatment of people with sleep-disorders. PUBLIC HEALTH RELEVANCE: Sleep disorders and sleep deprivation are major unmet public health problems. This proposal aims to add to our understanding of sleep regulation, in order to enhance the diagnosis and treatment of patients with sleep disorders.

描述（由申请人提供）：这项研究的长期目标是了解睡眠和类似睡眠状态的遗传调节。睡眠觉醒法规包括时钟时机，睡眠发作和抵消信号。睡眠状态的执行需要感觉门控，这是指在睡眠过程中降低反应性的现象。感官彩控是一个不受欢迎的睡眠的基本特性，它将其与安静的觉醒区分开。该提案旨在使用秀丽隐杆线虫模型生物体来提高我们对感官门控的机械理解。这种方法是研究嗜睡时期，这是秀丽隐杆线虫生命周期中发生的类似睡眠时期。在这一赠款期间，要测试的全球假设是EGL-4/PKG和CAMP信号在感觉神经元中作用起作用，以调节莱萨尔古斯期间的感觉输入，而降低了感觉输入促进了睡眠状的行为。该全球假设将通过四个特定目标进行检验。具体目标1将检验以下假设：调节嗜血率期间感觉反应性的分子机制是调节化学强度适应的分子机制。该假设将通过评估在嗜光液中的感觉适应性缺陷与感觉门控缺陷之间的关联来检验。此外，我们将测试动物在嗜血杆菌期间是否比莱萨尔古斯（Lethargus）外部更容易适应。特定的目标2将检验以下假设：cAMP信号在感觉神经元中起作用以拮抗嗜睡过程中的感觉门控。该假设将通过表达通常在感觉神经元中降低营地的基因PDE-4来检验。此外，我们将评估EGL-4和PDE-4之间的基因顺序关系正在调节感觉门控。特定的目标3将检验感觉输入调节类似睡眠行为的假设。这第三个目标将通过检查对莱萨尔古斯期间的感觉输入以及突变体和降低感觉功能的操作的影响的影响。最终的特定目的将执行遗传筛选，以识别EGL-4功能突变体增益中增强睡眠类似行为所需的基因。鉴于睡眠和睡眠状态的系统发育保护以及CGMP和CAMP依赖性信号通路的保存，这些实验很可能会阐明其他物种的睡眠调节。对睡眠调节的理解的提高将增强睡眠抑制患者的诊断和治疗。公共卫生相关性：睡眠障碍和睡眠剥夺是主要未满足的公共卫生问题。该建议旨在增加我们对睡眠调节的理解，以增强睡眠障碍患者的诊断和治疗。