Substrates of Cul3 and Insomniac for Sleep and Memory

项目摘要 自闭症谱系障碍是最常见的神经发育障碍之一， 42名男孩和1 189名女孩，并提出了一个紧迫和日益增长的公共卫生挑战。许多自闭症风险 基因已经被确定，但尚不清楚单个基因的突变如何导致不同的行为。 自闭症的改变，包括广泛的睡眠障碍和学习和认知缺陷。我们 我假设，至少对于自闭症风险基因的一个子集，多个下游分子的失调， 一些通路在神经元发育期间，另一些在更成熟的大脑中，是不同行为的基础。 自闭症的各个方面。由于许多自闭症风险基因是高度保守的， 果蝇代表了利用强大的遗传工具来剖析潜在机制的机会 自闭症我们在果蝇中的研究证明了Cullin-3（Cul 3）泛素连接酶、BTB 衔接蛋白Insomniac（Inc）和睡眠-觉醒周期的调节。我们的研究将利用 果蝇的遗传操作，以阐明Cul 3-Inc的影响机制和底物 睡眠和其他行为的复杂性。通过提高我们对细胞内的变化 泛素化途径导致睡眠功能障碍和认知缺陷，我们的研究可能最终 深入了解自闭症和其他神经系统疾病的病因。

PROJECT SUMMARY Autism spectrum disorders are among the most common neurodevelopmental disorders, affecting 1 in 42 boys and 1 in 189 girls, and present an urgent and growing public health challenge. Numerous autism risk genes have been identified, yet it is not clear how mutations in single genes cause the diverse behavioral alterations in autism, including pervasive sleep disturbances and deficits in learning and cognition. We hypothesize that, at least for a subset of autism risk genes, the dysregulation of multiple downstream molecular pathways, some during neuronal development and others in the more mature brain, underlie distinct behavioral aspects of autism. Because many autism risk genes are highly conserved, animal models such as the fruit fly Drosophila represent an opportunity to leverage powerful genetic tools to dissect mechanisms underlying autism. Our studies in Drosophila demonstrated a link between the Cullin-3 (Cul3) ubiquitin ligase, the BTB adaptor protein Insomniac (Inc), and the regulation of sleep–wake cycles. Our proposed research will utilize genetic manipulations in Drosophila to elucidate mechanisms and substrates underlying the impact of Cul3-Inc complex on sleep and other behaviors. By improving our understanding of how alterations in cellular ubiquitination pathways contribute to sleep dysfunction and cognitive deficits, our studies may ultimately provide insight into the etiology of autism and other neurological disorders.