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， 增加车辆碰撞的风险。这背后的基本机制 睡眠是未知的。目前，有人提出， 这是由促进睡眠的分子积累造成的。虽然若干 这些分子已经被识别出来，也许最清楚的证据是 腺苷。然而，我们不知道腺苷水平如何在关键的 大脑区域与睡眠/觉醒周期有关， 在大脑中是否有区域特异性 调控这一建议的基本概念是， 参与腺苷代谢（和/或核苷代谢）的酶的调节 与昼夜节律系统和睡眠的关系 体内平衡在设定腺苷水平方面起主要作用， 睡眠需要。这种假设的机制提供了一种强大的，新颖的方法， 实现睡眠和昼夜节律系统之间的相互作用。这 假设将在一系列补充研究中得到解决， 两所大学的研究人员（宾夕法尼亚大学和 马尼托巴大学），他们有互补的技能。在一系列的 研究，我们将直接测量总腺苷水平在几个 与睡眠相关的不同大脑区域，以及这些水平如何变化 在不同的睡眠剥夺持续时间之后。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）， 与睡眠相关的大脑区域。我们将研究的相对作用 昼夜节律和睡眠稳态系统介导这种变化。到 解决腺苷酶本身可能是如何调节的，我们将 在另一系列的研究中， 与mRNA丰度的改变相关， 内切酶mRNA分析也将用于评估是否类似 核苷转运蛋白发生时间变化。所有这些研究 将在老鼠身上进行。然而，我们的假设预测， 不同的昼夜分布的睡眠/觉醒周期将有 脑区腺苷及其酶的不同昼夜变化 与睡眠控制有关。这种动物是阿登·德古斯，我们 将在我们的最终方案中说明是否存在预测的差异 腺苷及其代谢酶的昼夜变化， 与老鼠相比。这些研究将提供一个 全面了解大脑腺苷是如何被调节的， 睡眠的需要。