Role of hypocretin/histamine in Narcolepsy/EDS disorders

描述(由申请人提供)：这项修订提案的主要目标是加深我们对下丘脑泌素/组胺相互作用在控制觉醒中的理解，以及它们各自参与人类发作性睡病和其他日间过度嗜睡(EDS)障碍的病理生理学，以改进人类的治疗方式。由于动物和人类研究的最新进展，现已证明下丘脑泌素(食欲素)配体的产生受损是大多数人类发作性睡病-猝倒的主要病理生理机制。然而，关于下丘脑肌素缺乏如何导致EDS和猝倒的机制很大程度上是未知的。一系列实验表明，组胺能系统是介导竹红菌素促醒作用的最重要的执行系统之一。我们还发现，在发作性睡病的犬模型中，大脑组胺能水平显著降低。因此，几乎可以肯定的是，更好地了解生理和药理作用，下丘脑泌素和组胺的相互作用将导致开发出更好的治疗人类睡眠障碍的选择。在修订后的提案中，我们将(1)研究组胺能系统作为关键的输出神经递质系统之一的生理学作用，该系统是介导下丘脑克汀素对觉醒和其他生理功能的影响的关键输出神经递质系统之一；(2)研究组胺水平和脑内组胺释放的变化；(3)利用下丘脑克汀素配基缺乏的发作性睡病小鼠模型，评估组胺能化合物对睡眠和猝倒的影响。我们相信，这些研究的结果将带来关于下丘脑泌素/组胺相互作用在发作性睡病和其他EDS障碍中的作用的新见解，以及更好的人类治疗方式。

DESCRIPTION (provided by applicant): The primary goal of this revised proposal is to further our understanding of hypocretin/histamine interaction in the control of wakefulness and their respective involvement in the pathophysiology of human narcolepsy and other excessive daytime sleepiness (EDS) disorders, in order to improve treatment modalities in humans. As a result of recent progress in animal and human studies, it has now been demonstrated that impaired hypocretin (orexin) ligand production is a major pathophysiological mechanism for most human narcolepsy-cataplexy. However, the mechanisms of how hypocretin deficiency induces EDS and cataplexy are largely unknown. A series of experiments have suggested that the histaminergic system is one of the most important executive systems for mediating the wake-promoting effects of hypocretin. We also found that brain histaminergic levels are significantly reduced in the canine model of narcolepsy. It is therefore all but guaranteed that a better understanding of the physiological and pharmacological roles hypocretin and histamine interactions will lead to the development of better treatment options for sleep disorders in humans. In the revised proposal, we will (1) study physiological roles of the histaminergic system as one of the critical output neurotransmitter systems that mediate the effects of hypocretin on wakefulness and other physiological functions, (2) study changes in histamine levels and release in the brains of hypocretin cell- targeting hypocretin-deficient narcoleptic mice, and (3) evaluate the effects of histaminergic compounds on sleep and cataplexy using the hypocretin-ligand deficient mouse model of narcolepsy. We believe that results from these studies will bring new insights regarding the roles of the hypocretin/histamine interaction in narcolepsy and other EDS disorders and better treatment modalities in humans.