THE MECHANISMS OF ALTERATIONS IN SLEEP WITH AGE

睡眠随年龄变化的机制

• 批准号: 6486856
• 负责人: Allan I Pack
• 金额: $ 11.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6486856
• 关键词: aging; circadian rhythms; neuroregulation; sleep; sleep disorders

This program of research is directed at elucidating the fundamental mechanisms which lead to alterations in the circadian and sleep promoting system with age. Such changes with age contribute to the high prevalence of sleep disorders in the elderly. We propose to address this issue at the most fundamental level and determine the age-related changes in the molecular mechanisms for these processes. Studies will both address changes with age in known processes, as well as address hypotheses to further our understanding of the mechanisms with age in known processes, as well as address hypotheses to further our understanding of the mechanisms involved. We plan studies in both Drosophila and rats. The former are studied since knowledge of the molecular basis of the circadian block is more complete, and there is growing evidence for an analogy of their rest-like period and sleep. Rats are used since the data on the neuronal circuitry are most complete, and we will investigate molecular mechanisms within the framework of the circuitry involved. In Project 1, we plan to study changes in the molecular mechanisms of the circadian clock in Drosophila. Studies will involve both investigating in vitro and in vivo, using new transgenic technology, alterations with age in the circadian rhythm of expression of the period and timeless genes. These studies will also investigate control of the rest period in Drosophila as an analog of sleep. The effect of manipulating the adenosine system pharmacologically on rest/activity will be studied. Adenosine, a sleep promoting molecule will be the major focus of Subprojects 0002 and 0002 which will be conducted in rats. Using unique facilities, we will study the levels of adenosine in key brain regions in young and old rats and address whether adenosine changes with age and/or in relationship to the duration of prior wakefulness. Adenosine levels are controlled by a complex metabolic system. Enzymes and transporters for adenosine could themselves change with age and/or diurnal effects. This will be addressed in these two projects by studying changes in the various components of the adenosine system t a molecular level Subproject 0002 and how changes in these components alter adenosine in the brain regions relevant to sleep (Subproject 0002). Thus, this Program Project is a comprehensive, integrated series of novel studies to address the changes with age in the sleep and circadian system at a fundamental level. The projects are supported by two cores- an Administrative and Rodent Behavioral and Assessment and Biostatistical Core. Common behavioral assessment protocols and biostatistical approaches facilitate a unique approach for this program of research.

该研究项目旨在阐明导致昼夜节律和睡眠促进系统随年龄变化的基本机制。这种随年龄的变化导致老年人睡眠障碍的高发。我们建议从最基本的层面解决这个问题，并确定这些过程的分子机制中与年龄相关的变化。研究将解决已知过程中随年龄变化的问题，并提出假设以进一步了解已知过程中随年龄变化的机制，并提出假设以进一步了解所涉及的机制。我们计划在果蝇和大鼠中进行研究。人们对前者进行了研究，因为对昼夜节律阻滞的分子基础的了解更加完整，并且越来越多的证据表明它们的休息期和睡眠之间存在类比。使用大鼠是因为关于神经元回路的数据是最完整的，我们将研究所涉及的回路框架内的分子机制。在项目1中，我们计划研究果蝇生物钟分子机制的变化。研究将涉及利用新的转基因技术进行体外和体内研究，研究周期和永恒基因表达的昼夜节律随年龄的变化。这些研究还将调查果蝇对休息时间的控制，将其作为睡眠的模拟。将研究药理学操纵腺苷系统对休息/活动的影响。腺苷，一种促进睡眠的分子，将成为在大鼠中进行的子项目 0002 和 0002 的主要焦点。使用独特的设施，我们将研究年轻和年老大鼠关键大脑区域的腺苷水平，并解决腺苷是否随着年龄和/或与先前清醒持续时间的关系而变化。腺苷水平由复杂的代谢系统控制。腺苷的酶和转运蛋白本身可能会随着年龄和/或昼夜影响而变化。这两个项目将通过研究分子水平子项目 0002 中腺苷系统的各种成分的变化以及这些成分的变化如何改变与睡眠相关的大脑区域中的腺苷（子项目 0002）来解决这个问题。因此，该计划项目是一系列全面、综合的新颖研究，旨在从根本上解决睡眠和昼夜节律系统随年龄的变化。这些项目由两个核心支持——行政和啮齿动物行为与评估以及生物统计核心。常见的行为评估方案和生物统计方法促进了该研究计划的独特方法。