Role of hypocretin/histamine in Narcolepsy/EDS disorders

描述（由申请人提供）：本修订提案的主要目标是进一步了解下丘脑泌素/组胺在控制觉醒中的相互作用及其各自参与人类发作性睡病和其他过度日间嗜睡（EDS）疾病的病理生理学，以改善人类治疗方式。作为动物和人类研究的最新进展的结果，现在已经证明，受损的下丘脑分泌素（食欲素）配体产生是大多数人发作性睡病的主要病理生理机制。然而，下丘脑泌素缺乏如何诱导EDS和cataemia的机制在很大程度上是未知的。一系列实验表明，组胺能系统是介导下丘脑泌素促醒作用的最重要的执行系统之一。我们还发现，在发作性睡病犬模型中，脑组胺能水平显著降低。因此，几乎可以保证，更好地了解下丘脑泌素和组胺相互作用的生理和药理作用将导致开发更好的人类睡眠障碍治疗方案。在修订后的提案中，我们将（1）研究组胺能系统的生理作用，组胺能系统是介导下丘脑泌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）研究下丘脑泌素细胞靶向下丘脑泌素缺陷发作性睡眠小鼠脑中组胺水平和释放的变化，和（3）使用发作性睡病的下丘脑泌素配体缺陷小鼠模型评价组胺能化合物对睡眠和紧张症的作用。我们相信，这些研究的结果将带来新的见解，下丘脑泌素/组胺相互作用在嗜睡症和其他EDS疾病和更好的治疗方式在人类中的作用。

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.