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: 7261383
• 负责人: SEIJI NISHINO
• 金额: $ 31.02万
• 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/7261383
• 关键词: Adverse effects; Affect; Animals; Autoreceptors; Brain; Canis familiaris; Cataplexy; Cells; Condition; Development; Disease; Dopamine; Excessive Daytime Sleepiness; Financial compensation; Functional disorder; Goals; Histamine; Histamine Release; Human; Lead; Ligands; MJD1 protein; Measures; Mediating; Microdialysis; Modality; Modeling; Mus; Mutate; Mutation; Narcolepsy; Neurologic; Neurons; Neuropeptides; Neurotransmitters; Norepinephrine; Output; Pathology; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Production; Rattus; Reporting; Research Personnel; Rest; Role; Series; Serotonin; Sleep; Sleep Disorders; System; Techniques; Therapeutic; Transgenic Organisms; Wakefulness; Wild Type Mouse; human study; hypocretin; improved; insight; mouse model; neurotransmission; programs; research study; transmission process; vigilance

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）：这项修订的建议的主要目标是进一步了解降压素/组胺相互作用，以控制清醒及其各自参与人类麻醉症的病理生理学和其他过度白天嗜睡（EDS）疾病（EDS）疾病，以改善人类人类的治疗模态。由于动物和人类研究的最新进展，现在已经证明了降压素（Orexin）配体产生受损是大多数人类性睡病膜状膜片的主要病理生理机制。然而，低螺旋蛋白缺乏症如何诱导ED和瘫痪的机制在很大程度上尚不清楚。一系列实验表明，组敏能系统是介导降压素的唤醒作用的最重要的执行系统之一。我们还发现，在睡病犬模型中，脑组胺能水平显着降低。因此，几乎可以保证，对生理和药理学作用降压素和组胺相互作用的更好理解将导致人类睡眠障碍的更好治疗选择。 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使用发作性疾病的降压素缺陷小鼠模型，在睡眠和瘫痪上的化合物。我们认为，这些研究的结果将带来有关低螺旋蛋白/组胺相互作用在麻醉症和其他EDS疾病中的作用以及人类更好治疗方式的新见解。