Genetic Analysis of Sleep Disorders in Zebrafish

大塔里族10%的人患有慢性睡眠障碍，但调节睡眠的遗传方式是 很大程度上是未知的。下丘脑肌素/食欲素I信号缺陷与发作性睡病的关系 但这种疾病的有效治疗方法还没有找到。 找到了。此外，只有一小部分睡眠障碍与发作性睡病有关，这表明 其他控制睡眠和清醒的基因仍有待确定。这项提议的目标是 利用斑马鱼作为简单而经济的脊椎动物基因系统研究Hcrt Jsighaling的遗传学 好好睡一觉。斑马鱼是这些研究的一个很好的模型，因为它们适合于高通量 与无脊椎动物不同，基因筛查和TES有一个HCRT同源基因和基本的大脑结构来调节 沉睡的哺乳动物。 我已经证明，Hcrt的过度表达会导致斑马鱼幼体出现失眠样表型。以特定的目标 1，1将使用药物来确定Hcrt的遗传和神经机制 离子诱导这种表型？这些实验将使用小分子中鉴定的试剂。 我在这个授予的K99阶段执行的屏幕。这些实验的结果将会有所改善 对HCRT功能的认识可能会为S治疗慢性失眠提供依据。在具体目标2，1 我将在基因过度表达筛查中研究导致特定睡眠表型的分泌肽 在这笔赠款的K99阶段执行。这些实验将证实来自屏幕的结果和 描述潜在的调节睡眠的新的遗传机制。 我的长期职业目标是阐明：调节睡眠/清醒状态的遗传和神经机制，希望这一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绝佳环境，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出色的研究，还有几个实验室在其他模型系统中研究睡眠的调节。

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.