Role of Histamine in Narcolepsy/EDS Disorders

描述（由申请人提供）：组胺在嗜睡症/EDS障碍R 03小额研究赠款的作用是专为短期，高影响，低成本的研究。这项工作的目的是扩大初步数据表明，低CSF组胺水平的障碍，白天过度嗜睡。我们还将研究正常健康志愿者CSF组胺水平的昼夜波动。越来越多的动物研究表明，组胺在调节警觉性方面起着重要作用。这可能与发作性睡病有关，因为下丘脑泌素刺激组胺能传递，并且下丘脑泌素传递缺陷的发作性睡病犬也具有低中枢神经组胺含量。我们还从两个来源（我们自己的样本和日本合作者）获得了初步数据，表明下丘脑泌素缺乏的发作性睡病-紧张症患者的CSF组胺水平较低。然而，最有趣的是，我们还发现，在一个亚组的患者白天嗜睡，但在正常的下丘脑泌素水平的背景下，例如与特发性嗜睡症的CSF组胺减少。与睡眠呼吸暂停相关的日间嗜睡患者的水平正常。这一令人兴奋的初步结果表明，组胺可能在中枢介导的嗜睡的非下丘脑泌素依赖性综合征的病理生理学中发挥作用。我们的目标是使用大量现有的CSF样本扩展此数据集。我们还将进行探索性统计分析，以研究低CSF组胺水平的临床预测因素。一旦初步发现得到证实，并进行了额外的探索性分析，将通过进一步的拨款申请来探讨这种变化是否是这些患者白天嗜睡的主要或次要原因。由于几乎没有什么是已知的病理生理学非下丘脑泌素缺乏嗜睡症，我们相信这项工作是理想的适合一个小的赠款申请。

DESCRIPTION (provided by applicant): Role of Histamine in Narcolepsy/EDS Disorders R03 small research grants are designed for short-term, high impact, low cost studies. The goal of this proposed work is to extend on preliminary data indicating low CSF histamine levels in disorders of excessive daytime sleepiness. We will also study diurnal fluctuation in CSF histamine levels in normal, healthy volunteers. An increasing number of animal studies suggest that histamine plays a major role in regulating alertness. This may be relevant to narcolepsy since hypocretin stimulates histaminergic transmission and narcoleptic canines with deficient hypocretin transmission also have low central nervous histamine contents. We also have preliminary data from two sources (our own samples and from a Japanese collaborator) indicating low CSF histamine in human narcolepsy-cataplexy with hypocretin deficiency. Most interestingly however, we also found decreased CSF histamine in a subset of patients with daytime sleepiness, but in the context of normal hypocretin levels, for example with idiopathic hypersomnia. Patients with daytime sleepiness associated with sleep apnea had normal levels. This exciting preliminary result suggests that histamine may play a role in the pathophysiology of non-hypocretin dependent syndrome of centrally- mediated hypersomnolence. Our goal will be to extend this dataset using a large number of existing CSF samples. We will also conduct exploratory statistical analysis to study clinical predictors of low CSF histamine levels. Whether or not this change is primary or secondary to daytime sleepiness in these patients will be explored by further grant applications once the preliminary finding is confirmed and additional exploratory analysis have been conducted. As almost nothing is known on the pathophysiology of non- hypocretin deficient hypersomnias, we believe this work to be ideally suited for a small grant application.