Genetics of Sleep in Zebrafish

描述（由申请人提供）：多达10%的美国人患有慢性睡眠障碍，但控制睡眠和清醒状态的遗传机制在很大程度上仍然未知。拟议研究的长期目标是确定调节睡眠、清醒和觉醒的分泌蛋白。斑马鱼将被用作模型系统，因为它显示出清晰、可测量的睡眠和清醒行为，而且是唯一一种可行的脊椎动物系统。筛选将涉及几百种稳定的转基因斑马鱼系，这些斑马鱼系在诱导启动子下表达分泌的蛋白质。该库将通过斑马鱼资源中心提供，并筛选幼虫睡眠和清醒的调节因子。此外，还将测试对机械、化学、热和视觉线索的反应。候选品系将在发育和行为缺陷的二次筛选中进一步分析。分离的多肽将为解剖睡眠的分子和神经回路奠定基础。筛选还将提供可能影响人类睡眠障碍的候选途径，这些途径可以通过药物调节来治疗睡眠障碍。

DESCRIPTION (provided by applicant): As many as 10% of Americans suffer chronic sleep disturbances, but the genetic mechanisms that control sleep and wake states remain largely unknown. The long-range goal of the proposed studies is to identify secreted proteins that modulate sleep, wakefulness and arousal. Zebrafish will be used as a model system because it displays clear, measurable sleep and wake behaviors and is the only vertebrate system in which such a screen is feasible. The screen will involve the generation of several hundred stably transgenic zebrafish lines that express secreted proteins under an inducible promoter. The library will be made available through the zebrafish stock center and screened for modulators of larval sleep and wakefulness. In addition, the response to mechanical, chemical, thermal and visual cues will be tested. Candidate lines will be further analyzed in secondary screens for developmental and behavioral defects. The isolated peptides will form the foundation to dissect the molecular and neural circuits of sleep. The screen will also provide candidate pathways that might be affected in human sleep disorders and that could be modulated by drugs to treat sleep disorders.