Genetic Analysis of Sleep Disorders in Zebrafish

10%的hurhahs患有慢性睡眠障碍，但调节睡眠的基因m？ 大部分未知。下丘脑分泌素/食欲素i（Hcrt）信号缺陷导致发作性睡病的鉴定 提供了一个遗传enUry点进入睡眠障碍，但有效的治疗这种疾病还没有， found.此外，只有一小部分睡眠障碍与嗜睡症有关，这表明， 控制睡眠和觉醒的其他基因仍有待鉴定。本提案的目的是 利用斑马鱼作为一种简单、经济的脊椎动物模型系统，研究猪链球菌的遗传学 睡觉斑马鱼是这些研究的一个很好的模型，因为它们适合高通量 与无脊椎动物不同，它有一个Hcrt直系同源物和调节 睡眠中的哺乳动物 我已经表明，Hcrt过表达导致斑马鱼幼虫失眠样表型。具体目标 1，1将使用药理学试剂来确定Hcrt的遗传和神经机制， 这些实验将使用在小分子中鉴定的试剂， 这是我在K99项目中所做的一个屏幕。这些实验的结果将会改善 了解Hcrt的功能，可能为慢性失眠的基础提供线索。具体目标2.1 将研究分泌肽，导致特定的睡眠表型的基因过表达筛选，我 在K99阶段，这是一个很好的例子。这些实验将证实筛选结果， 描述了调节睡眠的潜在新遗传机制。 我的长期职业目标是阐明：调节睡眠/觉醒状态的遗传和神经机制，希望这些知识将导致睡眠障碍的治疗。加州理工学院是追求这一目标的优秀实验室，因为有几个实验室在行为遗传学和行为神经科学方面进行了杰出的研究，以及研究其他模型系统中睡眠调节的实验室。

Greater thari 10% of hurhahs suffer chronic sleep disorders, hut the genetic m¿:hanisims that regulate sleep are largely unknown. The identification of defective Hypocretin/Orexin i[Hcrt) signaling as a cause of narcolepsy provided ia genetic enUry point into sleepresearch.but an effective treatment for this disorder has not yet been found. Moreover, only a sniall fraction of sleep disorders are associated with narcolepsy, indicating that additional genes that control sleep and wakefulness remain to be identified. The objective of this proposal is to use zebrafish as a simpile and cost-effective vertebrate rnodel system to study the genetics of Hcrt Jsighaling andsleep. Zebrafish are an excellent model for these studies because they are amenable to high-throughput genetic screens and, unlike invertebra:tes, have a Hcrt ortholog and the basic brain stl-iictures that regulate sleepin mammals. I have shown that Hcrt overexpression causes an insomhia-like phenotype in zebrafish larvae. In Specific Aim 1,1 will use pharmacological agents to determine the genetic and neurologic mechanisms by which Hcrt dverexpress;ion induces this phenotype^ These experiments vvill use reagents identified in a small molecule screen that I performed during the K99 phase of this grant. The results of these experiments will improve understanding Of Hcrt function and may provide cIue:S to the basis of chronic insomnia. In Specific Aim 2,1 will study secreted peptides that caused specific sleep phenotypes in the genetic overexpression screen that I performed during the K99 phase of this grant. These experiments vyill confirm results frorh the screen and characterize potentially novel genetic mechanisms that regulate sleep. My long-term career goalis to elucidate: the genetic and neurologic mechanisms that regulate sleep/wake states, with the hope that this knowledge will lead to treatments for sleep disorders. Caltech is an excellent environnient to pursue this goal since there are several labs performing outstanding research in the genetics of behavior arid behavioral neuroscience, as well as labs studying the regulation of sleep in other model systems.