Effects of OX2R agonist and antagonist on sleep apnea

项目描述（由申请人提供）：该项目的长期目标是开发并商业化一种治疗睡眠呼吸暂停的药物。睡眠呼吸暂停是一种常见的医学病症，与白天过度嗜睡有关，是心血管发病率和死亡率的综合风险。目前，尚无有效的药物治疗睡眠呼吸暂停患者。来自临床和基础研究的越来越多的证据正在迅速接近这样一个概念，即食欲素的改变在睡眠呼吸暂停的病理中起作用。基础研究表明，食欲素直接参与呼吸控制，大脑中较低水平的食欲素伴随着呼吸暂停的频繁出现。这一证据支持进一步研究食欲素受体激动剂和拮抗剂对通气的直接作用；该研究还表明，应该建立一种细胞测定方法，为开发治疗睡眠呼吸暂停的药物铺平道路。该项目将确定食欲素-2受体（OX2R）激动剂和拮抗剂对小鼠睡眠呼吸暂停发生的影响，并将优化已建立的OX2R细胞系的基于细胞的检测方法。假设是OX2R激动剂预防睡眠呼吸暂停的发生，而OX2R拮抗剂产生呼吸暂停。本项目将在小鼠模型中采用体积脉搏描记法结合睡眠记录测量通气节律。动物将接受OX2R激动剂或激动剂加拮抗剂或对照剂治疗，如人工皮质脊髓液，通过脑室内注射。每天记录8小时的数据，计算睡眠呼吸暂停低通气指数（AHI）。将对基线和治疗期之间以及治疗组之间的比较进行评估。优化基于OX2R细胞的检测是本项目的二次研究。使用细胞培养方法和市售的基于细胞的检测试剂盒，该项目将测量细胞对OX2R激动剂和拮抗剂治疗的最佳反应。该项目的成功完成将证实或反驳OX2R激动剂预防睡眠呼吸暂停的假设；此外，它将为未来药物的开发创造一种基于细胞系的检测方法，最终可能导致有效的药物治疗睡眠呼吸暂停。

DESCRIPTION (provided by applicant): The long term goal of this project is to develop and commercialize a drug to treat sleep apnea. Sleep apnea is a common medical condition and associated with excessive daytime sleepiness and is a composite risk for cardiovascular morbidity and mortality. Presently, there are no effective pharmacotherapies for individuals with sleep apnea. Growing evidence from both clinical and basic research is quickly approaching the concept that alterations of orexins play a role in the pathology of sleep apnea. Basic research has shown that orexins are directly involved in respiratory control, and a lower level of brain orexins accompanies the frequent appearance of ventilationary pauses. This evidence supports the further study of the direct effects of orexin receptor agonists and antagonists on ventilation; it also suggests that a cell assay should be created to pave the way for the development of a pharmaceutical treatment of sleep apnea. This project will determine the effects of orexin-2 receptor (OX2R) agonists and antagonists on the occurrence of sleep apnea in a mouse model, and it will optimize an established cell-based assay of an OX2R cell line. The hypothesis is that OX2R agonists prevent the occurrence of sleep apnea, and OX2R antagonists produce apnea. The project will measure ventilation rhythm by the plethysmography method combined with sleep recording in the mouse model. Animals will be treated with OX2R agonists or agonists plus antagonists or a control agent, such as artificial corticospinal fluid, via intracerebroventricular injection. A sleep apnea-hypopnea index (AHI) will be calculated for a daily 8 hours of recording data. Comparisons between the baseline and the treatment periods as well as among treatment groups will be evaluated. Optimizing OX2R cell-based assay is the secondary study in this project. Using a cell culture method and a commercially available cell-based assay kit, the project will measure optimal cell response to the OX2R agonist and antagonist treatment. Successful completion of this project will either confirm or refute the hypothesis that OX2R agonists prevent sleep apnea; additionally, it will create a cell line-based assay for the future development of drugs that may eventually lead to effective pharmacotherapy for sleep apnea. PUBLIC HEALTH RELEVANCE: This project will evaluate the potential therapeutic effect of endogenous orexin receptor agonists on sleep apnea in a mouse model and optimize a established cell-based assay for further development in this new direction. Successful completion of this project will establish a strong and solid foundation for the Phase II development of lead compound research in the pharmaceutical treatment of sleep apnea.