Project 3

项目3

• 批准号: 8479255
• 负责人: Alexander Martinus Van der Linden
• 金额: $ 30.23万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8479255
• 关键词: Affect; Afferent Neurons; Alzheimer' s Disease; Animal Model; Animal Testing; Animals; Behavior; Behavioral; Biological; Biological Assay; Biological Clocks; Biological Models; Body Temperature; Body Temperature Changes; Brain; Caenorhabditis elegans; Circadian Rhythms; Computer software; Coupled; Cues; Exhibits; Gene Components; Gene Expression; Gene Expression Process; Genes; Genetic; Genetic Models; Genetic Screening; Genomics; Hour; Human; Hypoxia; Image; Lead; Light; Maps; Molecular; Molecular Profiling; Moods; Morbidity - disease rate; Mutation; Nematoda; Neural Pathways; Neurosciences; Organism; Output; Pathway interactions; Patients; Periodicity; Peripheral; Physiological; Physiology; Prevention; Process; Regulation; Research; Sensory; Sensory Process; Severities; Signal Transduction; Sleep; Stroke; System; Taxes; Techniques; Temperature; Temperature Sense; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Tissues; Work; circadian pacemaker; cyclic-nucleotide gated ion channels; design; insight; mRNA tagging; mutant; nervous system disorder; neural circuit; neurobehavioral; next generation; response; suprachiasmatic nucleus; tool; treatment strategy

Temperature control of the C. elegans circadian clock Daily (circadian) rhythms control multiple aspects of human behavior and physiology (e.g. sleep, body temperature) and disruption of these rhythms can either cause or affect the severity of most neurological disorders such as stroke and Alzheimer's disease. These circadian rhythms are driven by clocks in our brain and body that can be entrained by daily light and/or temperature cycles. In depth analyses have identified the physiological mechanisms comprising these light-entrained clocks in humans and most model organisms studied, but how temperature information controls these clocks is unclear. Our research has established the nematode Caenorhabditis elegans as a powerful genetic model system to study temperature control of the clock. In this proposed research, we will use genetic and genomic approaches as well as real-time imaging in C elegans to investigate the molecular mechanisms and neural pathways underlying temperature control ofthe circadian clock. Specific Aim 1 will develop a new real-time imaging system for recording and quantifying circadian rhythmicity in behavior and gene expression in freely moving C elegans. This imaging will be useful for mutant analysis and genetic screening of clock mutants. Specific Aim 2 will define the sensory neuron types that transmit temperature information to the clock(s). This will aid in understanding the sensory pathways that process and integrate environmental information to the clock. Specific Aim 3 will define the molecular components ofthe clock. These components are expected to encode for core-clock genes and components that process temperature information from the core-clock to clock-output genes. Specific Aim 4 will identify circadian genes expressed in single sensory neuron types with mRNAsequencing. Identification ofthe complete set of sensory genes regulated by the C elegans clock will determine the behavioral consequences of differential expression of genes that process environmental information to the clock. Understanding the inner workings ofthe circadian clock in great depth and the impacts on circadian time keeping should provide us with new avenues of treatment or prevention of neurobehavioral consequences of disrupted circadian timing.

C.温度控制优美生物钟 每日（昼夜）节律控制人类行为和生理的多个方面（例如睡眠、身体）。 温度）和这些节律的中断可以引起或影响大多数神经系统疾病的严重程度。 中风和阿尔茨海默病等疾病。这些昼夜节律是由我们大脑中的生物钟驱动的 和/或温度循环所携带的身体。深入分析发现， 在人类和大多数模式生物中， 研究，但如何温度信息控制这些时钟是不清楚的。我们的研究已经建立了 线虫作为一个强大的遗传模式系统，研究温度控制的 时钟在这项拟议的研究中，我们将使用遗传和基因组方法以及实时成像 研究温度控制的分子机制和神经通路 生物钟的变化Specific Aim 1将开发一种新的实时成像系统， 量化自由移动的线虫的行为和基因表达的昼夜节律。该成像 将有助于突变体分析和时钟突变体的遗传筛选。具体目标2将定义 感觉神经元类型，将温度信息传输到时钟。这将有助于理解 处理和整合环境信息到生物钟的感觉通路。第3章将 来定义生物钟的分子组成。这些组件预计将编码为核心时钟 基因和组件处理从核心时钟到时钟输出基因的温度信息。 特异性目标4将通过mRNA测序鉴定在单一感觉神经元类型中表达的昼夜节律基因。 鉴定由线虫生物钟调控的完整的感觉基因组， 确定处理环境的基因的差异表达的行为后果， 时钟的信息深入了解生物钟的内部运作， 对昼夜节律时间保持的影响应该为我们提供新的治疗或预防途径， 神经行为的后果打乱昼夜节律的时间。