REGULATION OF ADENOSINE IN RELATION TO SLEEP NEED

腺苷与睡眠需求的调节

• 批准号: 6657599
• 负责人: Allan I Pack
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657599
• 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 车辆撞车的风险增加。这是基本的基本机制 嗜睡是未知的。目前提议增加嗜睡 促进睡眠的分子的积累结果。而几个 已经确定了这样的分子，也许最明确的证据是 腺苷。但是，我们不知道关键的腺苷水平如何 大脑区域受到睡眠/唤醒周期的调节 大脑内是否有区域特异性 规定。该提议是基于基本观念 调节参与腺苷代谢的酶（和/或核苷 转运者）与昼夜节律的关系并入睡 稳态在设定腺苷水平方面起着重要作用 睡眠需要。这种假定的机制为 在睡眠和昼夜节律之间实现相互作用。这 假设将在一系列互补的研究中解决 两所大学的调查人员（宾夕法尼亚大学和 曼尼托巴省大学）具有互补的技能。一系列 研究，我们将直接测量几种腺苷水平 与睡眠有关的不同大脑区域以及这些层次如何变化 整天，随着不同的睡眠剥夺时间。在 其他研究，我们将确定相关的昼夜变化 酶（腺苷激酶，腺苷脱氨酶和5'-核苷酸酶） 与睡眠有关的大脑区域。我们将研究 昼夜节律和睡眠稳态系统调解这种变化。到 解决腺苷酶本身如何调节，我们将 在另一系列研究中的地址，酶活性的变化是否变化 与相关的mRNA丰度改变相关 酶。 mRNA分析还将用于评估是否相似 核苷转运蛋白发生时间变化。所有这些研究 将在老鼠中完成。但是，我们的假设将预测动物 他们的睡眠/唤醒周期有不同的昼夜分布 腺苷及其酶在大脑区域的不同昼夜变化 与睡眠控制有关。这样的动物是八颗多数，我们 将在我们的最终协议中解决是否存在预测差异 在腺苷及其代谢酶的昼夜变化中 物种与大鼠相比。综上所述，这些研究将提供 有关如何调节脑腺苷的全面图片 睡眠需要。