The Genetic Basis of Hypocretin Neuronal Specification.

描述（由申请人提供）：睡眠是一种进化上保守的行为，对神经性能和功能很重要，但调控睡眠的基因和神经元知之甚少。最典型的睡眠调节因子是下丘脑分泌素神经肽，它促进觉醒和抑制睡眠。下丘脑分泌素神经元的丧失导致嗜睡症，这是一种无法治愈的神经系统疾病，其特征是白天过度嗜睡和断断续续的睡眠/清醒状态。因此，下丘脑分泌素神经元在调节睡眠中起着至关重要的作用，但实际上对调节其功能的因素一无所知。在斑马鱼（Danio rerio）的初步研究中，已经鉴定出19个在下丘脑分泌素神经元中表达丰富的基因。我将测试假设，其中一些基因是必要的和/或足以指定下丘脑分泌素神经元的命运。确定这些因素将极大地扩展我们对下丘脑分泌素神经元发育的理解，并可能阐明这些神经元是如何组装成一个功能性睡眠回路的。最终，这些实验可能会导致新的治疗方法，防止或逆转发作性睡症患者的下丘脑分泌素神经元的损失。

DESCRIPTION (provided by applicant): Sleep is an evolutionarily conserved behavior that is important for neural performance and function, yet the genes and neurons that regulate sleep are poorly understood. The best-characterized sleep regulators are the hypocretin neuropeptides, which promote wakefulness and inhibit sleep. Loss of hypocretin neurons causes narcolepsy, an incurable neurological disorder characterized by excessive daytime sleepiness and fragmented sleep/wake states. Hypocretin neurons thus play a critical role in regulating sleep, but virtually nothing is known about factors that regulate their specification. Preliminary studies in the zebrafish, Danio rerio, have identified 19 genes with enriched expression in hypocretin neurons. I will test the hypothesis that some of these genes are necessary and/or sufficient to specify the hypocretin neuronal fate. Identifying such factors will greatly expand our understanding of hypocretin neuronal development, and may elucidate how these neurons are assembled into a functional sleep circuit. Ultimately, these experiments could lead to novel therapies that prevent or reverse the loss of hypocretin neurons in patients with narcolepsy. PUBLIC HEALTH RELEVANCE: Hypocretin neuropeptides play an evolutionarily conserved role in promoting wakefulness and inhibiting sleep. The loss of hypocretin neurons causes the sleep disorder narcolepsy, which has no known cure and is treated symptomatically. Using zebrafish as a simple vertebrate model, I will investigate the genetic basis of hypocretin neuronal development, which will improve our understanding of how sleep regulatory circuits are established and may lead to long-term, cellular therapies for narcolepsy.