Effects of OX2R agonist and antagonist on sleep apnea

描述(由申请人提供)：该项目的长期目标是开发一种治疗睡眠呼吸暂停的药物并将其商业化。睡眠呼吸暂停是一种常见的医学状况，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，还没有针对睡眠呼吸暂停患者的有效药物治疗方法。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，即食欲素的变化在睡眠呼吸暂停的病理中发挥了作用。基础研究表明，食欲素直接参与呼吸控制，脑部食欲素水平较低会经常出现呼吸暂停。这一证据支持进一步研究增食欲素受体激动剂和拮抗剂对呼吸的直接影响；它还建议建立细胞分析，为开发睡眠呼吸暂停的药物治疗铺平道路。该项目将确定食欲素-2受体(OX2R)激动剂和拮抗剂在小鼠模型中对睡眠呼吸暂停发生的影响，并将优化已建立的基于细胞的OX2R细胞系分析。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。该项目将在小鼠模型上通过体积描记法和睡眠记录相结合的方法来测量呼吸节律。动物将通过脑室内注射OX2R激动剂或激动剂加上拮抗剂或控制剂，如人造皮质脊髓液。每天8小时的记录数据将计算出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OX2R细胞检测是本项目的二次研究。使用细胞培养方法和商业上可用的基于细胞的分析试剂盒，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驳斥OX2R激动剂预防睡眠呼吸暂停的假设；此外，它还将为未来药物的开发创造一种基于细胞系的分析，最终可能导致睡眠呼吸暂停的有效药物治疗。 公共卫生相关性：该项目将评估内源性增食欲素受体激动剂对小鼠睡眠呼吸暂停的潜在治疗效果，并优化已建立的基于细胞的检测方法，以便在这一新方向上进一步发展。该项目的顺利完成将为药物治疗睡眠呼吸暂停的先导化合物研究的二期开发奠定坚实的基础。

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.