Interdisciplinary Studies of Sleep and Circadian Rhythms

睡眠和昼夜节律的跨学科研究

• 批准号: 10512267
• 负责人: Michael Warren Young
• 金额: $ 59.32万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512267
• 关键词: Advanced Sleep Phase Syndrome; Affect; Age; Aging; Alleles; Anxiety Disorders; Area; Behavior; Biochemical; Biological; Biological Assay; Blood - brain barrier anatomy; Cell Culture Techniques; Cell physiology; Chronic Disease; Chronic Insomnia; Circadian Rhythms; Clinical; Complement; Databases; Diabetes Mellitus; Disease; Drosophila genus; Etiology; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetic Variation; Genetic study; Hereditary Disease; Heritability; Human; Individual; Interdisciplinary Study; Investigation; Link; Longevity; Meleagris gallopavo; Molecular; Molecular Genetics; Mood Disorders; Morphology; Mutation; Narcolepsy; Neuroglia; Obesity; Orthologous Gene; Pathway interactions; Pattern; Periodicity; Permeability; Phase; Phenotype; Physiological; Population; Proteins; RNA Interference; Recovery; Regulation; Research; Role; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Testing; Universities; Variant; aged; awake; base; behavioral phenotyping; behavioral study; biophysical properties; blood-brain barrier function; blood-brain barrier permeabilization; casein kinase I; circadian; circadian pacemaker; clinically significant; comorbidity; comparative; cryptochrome; economic impact; exome; fly; gene function; genome-wide; human error; human subject; improved; insight; kindred; molecular sequence database; mutant; novel strategies; prediction algorithm; preservation; response; sleep pattern; tool; transcriptome sequencing

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.

项目概要/摘要 我们之前在果蝇中进行的基因筛查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，insomniac、cullin3 和 nedd8，是 在果蝇的形成血脑屏障的神经束膜下神经胶质细胞中表达，并且 inc、cullin3 和 nedd8 中屏障的形态和生物物理特性发生改变 突变体。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， 评估整个可用睡眠突变体范围以及老年人与年轻人的屏障功能 苍蝇，并探索睡眠和经典屏障调节之间的调节相互作用的证据 基因。大多数果蝇睡眠突变体都会严重缩短寿命。我们将确定是否 延长寿命的突变还可以改善屏障功能和睡眠持续时间 突变体。在我们提出的研究的第二个分支中，我们将研究生物钟的作用 人类睡眠障碍中常见的基因。我们最近发现了一个突变 生物钟基因 CRY1 与某种形式的睡眠相位延迟障碍相关 (DSPD) 影响全球约百分之一的人。我们的研究结果提出了一种新颖的 探索类似常见睡眠障碍的遗传性的方法：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异 细胞表型分析。与细胞昼夜节律改变相关的普遍等位基因 培养测定也将通过由以下方法鉴定的携带者受试者的行为表型来研究 土耳其安卡拉比尔肯特大学的合作者。睡眠障碍常常伴随着 慢性疾病，包括糖尿病、肥胖症或某些情绪和焦虑障碍。虽然 在这种情况下，通过传统方法很难确定因果关系，我们将采用 具有特定遗传变异的个体的深层生理和行为表型 在与特定合并症的联系测试中影响睡眠。这些研究可能会显着丰富 我们对人类生物钟调节的生物途径的理解以及 基本疾病病因。