Hypocretins and Their Role in the Control of Sleep

描述：(改编自申请者的摘要)失眠是 美国普遍存在的睡眠障碍，影响了大约10%的 人口。其他睡眠障碍包括阻塞性睡眠呼吸暂停，不宁腿 综合症和嗜睡症。最近，G蛋白偶联受体的一个突变 下丘脑肌素受体-2与犬发作性睡病的发生有关。 此外，小鼠神经肽下分泌素基因的破坏 导致这些小鼠患发作性睡病。这两个结果有 关注作为睡眠重要调节器的下丘脑素系统 在人类身上。申请组织Neurocrine Biosciences已经开发出一种 抗下丘脑皮质激素受体-2的系列小分子拮抗剂。的关注点 这一应用首先表征了这些小分子拮抗剂 体外培养。拮抗剂将在竞争性结合分析中进行测试 基于细胞的功能分析。第二，小分子拮抗剂将是 在体内进行了测试。将建立大鼠和狗的模型并对其进行评估 小分子拮抗剂对睡眠和觉醒的影响。这个 小分子拮抗剂作用的特异性将进一步 比较正常犬和突变的下克汀病受体-2的评价 有嗜睡症的狗。这项研究的结果将对确定 下丘脑肌素受体拮抗剂在睡眠控制中的有效性。 这些研究也将有助于为未来做好准备。 下丘脑角蛋白受体-2激动剂的研究进展 嗜睡症。 建议的商业应用： 这项研究的潜在应用是在失眠领域。 (估计有10%的人口患有慢性失眠)。基座 根据现有的数据，可以合理地假设下丘脑肌素受体 拮抗剂将促进非快速眼动睡眠和快速眼动睡眠。

DESCRIPTION: (Adapted from the Applicant's Abstract) Insomnia is one of the more prevalent sleep disorders in the US, affecting about 10 percent of the population. Other sleep disorders include obstructive sleep apnea, restless leg syndrome and narcolepsy. Recently, a mutation in the G-protein coupled receptor hypocretin receptor-2 has been linked to the development of narcolepsy in dogs. In addition, the disruption of a gene in mice for the neuropeptide hypocretin led to the development of narcolepsy in those mice. These two results have focused attention on the hypocretin system as an important modulator of sleep in humans. The applicant organization, Neurocrine Biosciences, has developed a series of small molecule antagonists to the hypocretin receptor-2. The focus of this application is to first characterize these small molecule antagonists in vitro. The antagonists will be tested in competitive binding assays and cell-based functional assays. Second, the small molecule antagonists will be tested in vivo. Both rat and dog models will be set up and evaluated for the effect of the small molecule antagonists on sleep and wakefulness. The specificity of the effects of the small molecule antagonists will be further evaluated by comparing normal dogs with hypocretin receptor-2 mutated narcoleptic dogs. The results of this study will be valuable in determining the effectiveness of a hypocretin receptor antagonist in the control of sleep. These studies will also help to prepare the groundwork for the future development of hypocretin receptor-2 agonist as a possible treatment for narcolepsy. PROPOSED COMMERCIAL APPLICATION: A potential application for the research proposed is in the field of insomnia (an estimated 10% of the population suffers from chronic insomnia). Based on the available data, it is reasonable to hypothesize that hypocretin receptor antagonists will promote non-REM and REM sleep.