Hypocretins and Their Role in the Control of Sleep

下丘脑分泌素及其在睡眠控制中的作用

• 批准号: 6338124
• 负责人: RICHARD A MAKI
• 金额: $ 11.79万
• 依托单位: NEUROCRINE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338124
• 关键词: G protein; REM sleep; bioassay; dogs; electrodes; electroencephalography; electromyography; inhibitor /antagonist; laboratory rat; monitoring device; narcolepsy; neuropeptides; peptide chemical synthesis; polymerase chain reaction; receptor binding; receptor coupling; receptor expression; sleep; sleep disorders; tissue /cell culture; wakefulness

DESRIPTION: (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.

描述：（改编自申请人的摘要）失眠是最常见的疾病之一 美国普遍存在睡眠障碍，影响了大约 10% 的人 人口。其他睡眠障碍包括阻塞性睡眠呼吸暂停、不宁腿 综合征和发作性睡病。最近，G蛋白偶联受体发生突变 下丘脑分泌素受体 2 与狗的发作性睡病的发生有关。 此外，小鼠神经肽下丘脑分泌素基因的破坏 导致这些小鼠出现发作性睡病。这两个结果有 重点关注下丘脑分泌素系统作为睡眠的重要调节剂 在人类中。申请组织 Neurocrine Biosciences 开发了一种 系列下丘脑分泌素受体 2 的小分子拮抗剂。重点是 该应用首先是表征这些小分子拮抗剂 体外。拮抗剂将在竞争性结合测定中进行测试 基于细胞的功能测定。其次，小分子拮抗剂 体内测试。将建立大鼠和狗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 小分子拮抗剂作用的特异性将进一步得到证实 通过比较具有下丘脑分泌素受体 2 突变的正常狗进行评估 发作性睡病的狗。这项研究的结果对于确定 下丘脑分泌素受体拮抗剂在控制睡眠方面的有效性。 这些研究也将有助于为未来奠定基础 开发下丘脑分泌素受体 2 激动剂作为一种可能的治疗方法 发作性睡病。 拟议的商业应用： 该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症）。基于 根据现有数据，可以合理地假设下丘脑分泌素受体 拮抗剂会促进非快速眼动睡眠和快速眼动睡眠。