Role of hypocretin/histamine in Narcolepsy/EDS disorders

下丘脑分泌素/组胺在发作性睡病/EDS 疾病中的作用

• 批准号: 7149390
• 负责人: SEIJI NISHINO
• 金额: $ 31.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-14 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149390
• 关键词: biological signal transduction; cataplexy; cerebrospinal fluid; executive function; gene deletion mutation; gene expression; gene targeting; genetically modified animals; histamine; laboratory mouse; laboratory rat; narcolepsy; neurotransmitters; orexin; sleep disorders; wakefulness

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.

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分泌素/组胺在控制觉醒中的相互作用，以及它们各自在人类发作性睡病和其他日间过度嗜睡（EDS）疾病的病理生理学中的作用，以改善人类的治疗方式。由于动物和人类研究的最新进展，现已证明下丘脑分泌素（食欲素）配体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，下丘脑分泌素缺乏如何诱发 EDS 和猝倒的机制尚不清楚。一系列实验表明，组胺能系统是介导下丘脑分泌素促醒作用的最重要的执行系统之一。我们还发现，在犬类发作性睡病模型中，大脑组胺能水平显着降低。因此，几乎可以保证，更好地了解下丘脑分泌素和组胺相互作用的生理和药理学作用将有助于开发出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）研究组胺能系统作为关键输出神经递质系统之一的生理作用，介导下丘脑分泌素对觉醒和其他生理功能的影响，（2）研究组胺水平和释放的变化下丘脑分泌素细胞靶向缺乏下丘脑分泌素的发作性睡病小鼠的大脑，以及（3）使用以下方法评估组胺能化合物对睡眠和猝倒的影响下丘脑分泌素配体缺陷的发作性睡病小鼠模型。我们相信，这些研究的结果将为下丘脑分泌素/组胺相互作用在发作性睡病和其他 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。