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，但对调节睡眠的基因和神经元了解甚少。最具特征的睡眠调节剂是下丘脑泌素神经肽，它促进觉醒并抑制睡眠。下丘脑泌素神经元的缺失导致发作性睡病，这是一种无法治愈的神经系统疾病，其特征在于白天过度嗜睡和碎片化的睡眠/觉醒状态。因此，下丘脑泌素神经元在调节睡眠中起着关键作用，但实际上对调节其特化的因素一无所知。在斑马鱼（Danio rerio）中的初步研究已经鉴定出19个在下丘脑泌素神经元中富集表达的基因。我将测试的假设，这些基因中的一些是必要的和/或足以指定下丘脑泌素神经元的命运。识别这些因素将大大扩展我们对下丘脑泌素神经元发育的理解，并可能阐明这些神经元如何组装成功能性睡眠回路。最终，这些实验可能导致新的疗法，防止或逆转发作性睡病患者下丘脑泌素神经元的损失。 公共卫生相关性：下丘脑泌素神经肽在促进觉醒和抑制睡眠方面发挥进化保守的作用。下丘脑泌素神经元的缺失导致睡眠障碍发作性睡病，这种病没有已知的治愈方法，只能通过药物治疗。使用斑马鱼作为一个简单的脊椎动物模型，我将研究下丘脑泌素神经元发育的遗传基础，这将提高我们对睡眠调节回路如何建立的理解，并可能导致嗜睡症的长期细胞疗法。

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.