REGULATION OF ADENOSINE IN RELATION TO SLEEP NEED

腺苷与睡眠需求的调节

• 批准号: 6349176
• 负责人: Allan I Pack
• 金额: $ 21.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349176
• 关键词: 5' nucleotidase; Rodentias; adenosine; adenosine deaminase; adenosine kinase; brain mapping; brain metabolism; circadian rhythms; laboratory rat; nucleotide metabolism; sleep; species difference

Sleep apnea is associated with excessive daytime sleepiness and hence an increased risk of vehicular crashes. The basic mechanism underlying this sleepiness is unknown. Currently it is proposed that increasing sleepiness results from accumulation of molecules that promote sleep. While several such molecules have been identified, perhaps the clearest evidence is for adenosine. We do not known, however, how adenosine levels in critical brain regions are regulated in relation to the sleep/wake cycle nor whether there is within the brain a regional specificity to this regulation. This proposal is based on the fundamental notion that regulation of enzymes involved in adenosine metabolism (and/or nucleoside transporters) in relationship to the circadian system and to sleep homeostasis play a major role in setting adenosine levels in relation to sleep need. This postulated mechanism provides a powerful, novel method to achieve interaction between the sleep and circadian systems. This hypothesis will be addressed in a complementary series of studies with investigators at two universities (University of Pennsylvania and University of Manitoba) who have complementary skills. In one series of studies, we will directly measure total adenosine levels in several different brain regions relevant to sleep, and how these levels changes across the day and following different durations of sleep deprivation. In other studies, we will determine the diurnal changes in the relevant enzymes (adenosine kinase, adenosine deaminase, and 5'-nucleotidase) in brain regions relevant to sleep. We will study the relative role of the circadian and sleep homeostatic system in mediating such changes. To address how the adenosine enzymes might themselves be regulated, we will address, in another series of studies, whether changes in enzyme activity are correlated with alterations in mRNA abundance for the relevant enzymes. mRNA analysis will also be used to assess whether similar temporal changes occur in nucleoside transporters. All of these studies will be done in rats. Our hypothesis would predict, however, that animals with different diurnal distributions of their sleep/wake cycles will have different diurnal variations in adenosine and its enzymes in brain regions relevant for sleep control. Such an animal is the Octodon degus and we will address in our final protocol whether there is predicted differences in the diurnal changes in adenosine and its enzymes of metabolism in this species as compared to rat. Taken together, these studies will provide a comprehensive picture about how brain adenosine is regulated in relation to sleep need.

睡眠呼吸暂停与白天过度嗜睡有关，因此 增加了车辆相撞的风险。这背后的基本机制是 困倦是未知的。目前，有人建议增加睡意 这是促进睡眠的分子积累的结果。虽然有几个 这样的分子已经被发现，也许最清楚的证据是 腺苷。然而，我们不知道腺苷水平是如何在关键的 大脑区域受到与睡眠/清醒周期相关的调节 在大脑中是否存在区域特异性 监管。这项提议是基于这样一个基本概念： 腺苷(和/或核苷)代谢相关酶的调节 转运体)与昼夜节律和睡眠的关系 动态平衡在设定腺苷水平方面起着重要作用 睡眠需求。这种假定的机制提供了一种强大的、新颖的方法来 实现睡眠和昼夜节律系统之间的互动。这 假说将在一系列补充性研究中加以阐述， 两所大学的调查人员(宾夕法尼亚大学和 马尼托巴大学)，他们有互补的技能。在一系列 研究中，我们将直接测量几个 大脑与睡眠相关的不同区域，以及这些水平是如何变化的 在不同的睡眠剥夺时间之后的一天中。在……里面 其他研究中，我们将确定相关的日变化 酶(腺苷激酶、腺苷脱氨酶和5‘-核苷酸酶) 大脑中与睡眠相关的区域。我们将研究 昼夜节律和睡眠平衡系统在调节这种变化中起作用。至 解决腺苷酶本身可能如何调节的问题，我们将 在另一系列研究中，解决了酶活性的变化 与相关基因mRNA丰度的变化相关 酵素。信使核糖核酸分析也将用来评估类似的 核苷转运体发生时间变化。所有这些研究 将在老鼠身上完成。然而，我们的假设预测，动物 具有不同的睡眠/觉醒周期的日分布 脑区腺苷及其酶的不同日变化 与睡眠控制相关。这样的动物就是奥顿德格斯，而我们 将在我们的最终协议中解决是否存在预测的差异 体内腺苷及其代谢酶的昼夜变化 与老鼠相比的物种。综上所述，这些研究将提供一个 脑内腺苷是如何被调节的 以满足睡眠需求。