Effects of OX2R agonist and antagonist on sleep apnea

OX2R激动剂和拮抗剂对睡眠呼吸暂停的影响

• 批准号: 8201939
• 负责人: PINGFU FENG
• 金额: $ 15.91万
• 依托单位: BIOFUNC RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201939
• 关键词: Adult; Agonist; Animals; Apnea; Appearance; Basic Science; Biological Assay; Blood; Brain; Brain Stem; Cell Culture Techniques; Cell Line; Cells; Central Sleep Apnea; Clinic; Clinical Research; Clinical Trials; Consult; Data; Dependency; Development; Environmental air flow; Excessive Daytime Sleepiness; Exhibits; Foundations; Future; Genes; Goals; Hour; Individual; Injection of therapeutic agent; Intrinsic factor; Investigation; Knockout Mice; Lead; Link; Liquid substance; Measures; Medical; Methods; Morbidity - disease rate; Muscle; Neurons; Obstructive Sleep Apnea; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Play; Plethysmography; Population; Production; Receptor Cell; Receptor Gene; Regulation; Reporting; Research; Respiratory Muscles; Role; Screening procedure; Sleep; Sleep Apnea Syndromes; Solid; Structure; Syndrome; Testing; Therapeutic Effect; Toxicity Tests; Wakefulness; base; cardiovascular risk factor; commercialization; drug development; hypocretin; indexing; mortality; mouse model; orexin 1 receptor; orexin A; orexin B; orexin B receptor; phase 1 study; prepro-orexin; pressure; prevent; receptor; research and development; respiratory; response; treatment duration

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.

描述（由申请人提供）：该项目的长期目标是开发和商业化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疾病，与白天过度嗜睡有关，是心血管发病率和死亡率的复合风险。目前，对于睡眠呼吸暂停患者还没有有效的药物治疗方法。越来越多的临床和基础研究证据正在迅速接近食欲素的改变在睡眠呼吸暂停的病理学中发挥作用的概念。基础研究表明，食欲素直接参与呼吸控制，较低水平的大脑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影响;它还表明，应创建细胞测定，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（OX 2 R）激动剂和拮抗剂对小鼠模型中睡眠呼吸暂停发生的影响，并将优化OX 2 R细胞系的已建立的基于细胞的测定。假设OX 2 R激动剂预防睡眠呼吸暂停的发生，而OX 2 R拮抗剂产生呼吸暂停。本研究将以小鼠为研究对象，采用体积描记法结合睡眠记录的方法来测量小鼠的通气节律。动物将通过脑室内注射用0X 2 R激动剂或激动剂加拮抗剂或对照剂（例如人工皮质脊髓液）处理。将计算每天8小时记录数据的睡眠呼吸暂停低通气指数（AHI）。将评价基线和治疗期之间以及治疗组之间的比较。优化基于OX 2 R细胞的检测方法是本项目的次要研究。使用细胞培养方法和市售的基于细胞的测定试剂盒，该项目将测量对OX 2 R激动剂和拮抗剂治疗的最佳细胞反应。 该项目的成功完成将证实或反驳OX 2 R激动剂预防睡眠呼吸暂停的假设;此外，它将为未来开发药物创造一种基于细胞系的检测方法，最终可能导致有效的睡眠呼吸暂停药物治疗。 公共卫生相关性：该项目将在小鼠模型中评估内源性食欲素受体激动剂对睡眠呼吸暂停的潜在治疗作用，并优化已建立的基于细胞的测定法，以进一步发展这一新方向。该项目的成功完成将为睡眠呼吸暂停药物治疗中先导化合物研究的第二阶段开发奠定坚实的基础。