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的是进一步了解下丘脑分泌素/组胺相互作用在觉醒控制中的作用，以及它们各自在人类发作性睡病和其他白天过度嗜睡（EDS）疾病的病理生理学中的作用，以改进人类的治疗方式。由于动物和人体研究的最新进展，现在已经证明下丘脑分泌素（食欲素）配体产生受损是大多数人类发作性睡症-猝倒的主要病理生理机制。然而，下丘脑泌素缺乏如何诱发EDS和中风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促醒作用的最重要的执行系统之一。我们还发现，在犬嗜睡症模型中，脑组胺能水平显著降低。因此，对下丘脑分泌素和组胺相互作用的生理和药理作用的更好理解将导致人类睡眠障碍的更好治疗选择的发展。在修订后的提案中，我们将(1)研究组胺能系统作为介导下丘脑分泌素对觉醒和其他生理功能影响的关键输出神经递质系统之一的生理作用；(2)研究下丘脑分泌素细胞靶向下丘脑分泌素缺乏的发作性睡小鼠大脑中组胺水平和释放的变化；(3)利用下丘脑分泌素配体缺陷小鼠模型，评价组胺能化合物对睡眠和猝睡的影响。我们相信，这些研究结果将为下丘脑分泌素/组胺相互作用在嗜睡症和其他EDS疾病中的作用带来新的见解，并为人类提供更好的治疗方式。

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.