Interdisciplinary Studies of Sleep and Circadian Rhythms

项目概要/摘要 我们先前在果蝇中进行的基因筛选发现了几种对果蝇有强烈影响的突变。 睡眠模式最近，我们发现其中三个基因，失眠症，cullin 3和nedd 8， 表达于形成血脑屏障的果蝇神经束膜下胶质细胞， 在inc、cullin 3和nedd 8中，屏障的形态和生物物理特性发生改变 变种人在我们提出的研究中，我们将测试经典屏障突变体对睡眠的影响， 在整个可用的睡眠突变体范围内以及老年人与年轻人中评估屏障功能 苍蝇，探索睡眠和经典的屏障调节之间的相互作用的证据 基因.大多数果蝇睡眠突变体严重缩短寿命。我们将决定 增加寿命的突变也改善了睡眠中的屏障功能和睡眠时间 变种人在我们研究的第二个分支中，我们将研究生物钟的作用 人类睡眠障碍的常见基因。我们最近发现了一种变异的 与一种睡眠期延迟紊乱有关的生物钟基因RISK 1 （DSPD）影响全球约1/100的个体。我们的研究结果表明， 探索类似常见睡眠障碍遗传性的方法：预测算法 将应用于几个大型人类外显子组数据库，以选择候选昼夜节律变体， 细胞表型分析与细胞中改变的昼夜节律相关的流行等位基因 培养分析也将通过对携带者受试者的行为表型进行研究， 土耳其安卡拉比尔肯特大学的合作者。睡眠障碍往往伴随着 慢性疾病，包括糖尿病、肥胖症或某些情绪和焦虑症。虽然 在这种情况下，因果关系很难通过传统方法建立，我们将采用 共享特定遗传变异的个体的深层生理和行为表型 在与特定共病的联系测试中影响睡眠。这些研究可以大大丰富 我们对人体生物钟调节的生物途径的理解， 基本疾病病因学。

Project Summary/Abstract Our genetic screens in Drosophila previously identified several mutations with strong effects on patterns of sleep. Recently we found that three of these genes, insomniac, cullin3 and nedd8, are expressed in the blood-brain-barrier-forming subperineurial glia of the fly, and that the morphological and biophysical properties of the barrier are altered in inc, cullin3, and nedd8 mutants. In our proposed studies we will test the effects of classical barrier mutants on sleep, evaluate barrier function across the entire range of available sleep mutants and in aged vs young flies, and explore evidence for regulatory interactions among sleep and classical barrier-regulating genes. Most Drosophila sleep mutants severely reduce longevity. We will determine whether mutations that increase longevity also improve barrier function and sleep duration in sleep mutants. In a second branch of our proposed research we will examine the role of circadian clock genes in commonly encountered disorders of human sleep. We recently discovered a mutation of the circadian clock gene CRY1 that is associated with a form of delayed sleep phase disorder (DSPD) that affects ~1 in 100 individuals worldwide. The results of our study suggest a novel approach for exploring the heritability of similarly common sleep disorders: Predictive algorithms will be applied to several large human exome databases to select candidate circadian variants for cellular phenotyping. Prevalent alleles that are associated with altered circadian rhythmicity in cell culture assays also will be studied by behavioral phenotyping of carrier subjects identified by collaborators at Bilkent University in Ankara, Turkey. Disordered sleep is often accompanied by chronic diseases including diabetes, obesity, or certain mood and anxiety disorders. Although causality in such instances has been difficult to establish by traditional approaches, we will employ deep physiological and behavioral phenotyping of individuals sharing specific genetic variations affecting sleep in tests for linkage to specific co-morbidities. These studies may significantly enrich our understanding of biological pathways regulated by circadian clocks in humans as well as fundamental disease etiologies.