Genetics of Sleep in Zebrafish

描述(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不清楚。这项拟议中的研究的长期目标是识别调节睡眠、清醒和唤醒的分泌蛋白。斑马鱼将被用作模型系统，因为它显示出清晰、可测量的睡眠和醒来行为，并且是唯一可以使用这种屏幕的脊椎动物系统。这项筛选将涉及到数百个稳定转基因斑马鱼品系的产生，这些斑马鱼品系在可诱导启动子下表达分泌蛋白。该文库将通过斑马鱼种群中心提供，并对幼虫睡眠和清醒的调节器进行筛选。此外，还将测试对机械、化学、热和视觉暗示的反应。候选品系将在二次筛查中进一步分析发育和行为缺陷。分离出的多肽将为剖析睡眠的分子和神经电路奠定基础。该屏幕还将提供可能在人类睡眠障碍中受到影响的候选途径，并可能受到治疗睡眠障碍的药物的调节。

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.