Center for Sleep in Autism Spectrum Disorder

自闭症谱系障碍睡眠中心

• 批准号: 10531469
• 负责人: JOACHIM F HALLMAYER
• 金额: $ 194.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531469
• 关键词: Age; Animal Genetics; Animal Model; Animals; Architecture; Basic Science; Behavior; Behavioral Symptoms; Biological; Brain; Caregivers; Child; Clinical; Cognition; Comparative Biology; Consensus; Development; Diphenhydramine; Disease; Double-Blind Method; Electroencephalography; Etiology; Foundations; Functional disorder; Genes; Genetic Models; Genetic study; Goals; Home; Human; Impairment; Link; Measures; Mission; Mus; Mutation; Neurobehavioral Manifestations; Neuronal Plasticity; Neurons; Participant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Pilot Projects; Placebo Control; Polysomnography; Public Health; REM Sleep; Randomized; Research; Research Personnel; Rest; Role; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Stereotyped Behavior; Structure; Symptoms; Synapses; Synaptic plasticity; Translations; Zebrafish; actigraphy; adolescent with autism spectrum disorder; aged; animal data; associated symptom; autism spectrum disorder; autistic children; awake; base; behavioral phenotyping; cognitive function; comorbidity; disorder control; experience; experimental study; gene function; human subject; improved; individuals with autism spectrum disorder; multimodality; neurodevelopment; neuron development; non rapid eye movement; programs; reduce symptoms; repetitive behavior; sex; sleep abnormalities; sleep onset; sleep physiology; sleep quantity; social communication; trait; translational approach; zolpidem

The mission of our proposed Autism Center of Excellence (ACE) is to examine if dysregulation of sleep is central to the development and exacerbation of symptoms in ASD. Animal data demonstrate that sleep is essential for the maturation of fundamental brain structures, neuronal development and synaptic plasticity. Sleep dysregulation is one of the most burdensome symptoms in individuals with ASD. Late sleep onset, frequent nighttime awakening, sleep fragmentation and abnormal sleep quantity hallmark sleep in ASD. Sleep EEG studies indicate less REM sleep and increased Non-REM Sleep. Despite its central role in brain development and function, sleep impairments are frequently considered as secondary. The main goal of our Center for Sleep in ASD is to determine if sleep disturbances reflect convergent pathways that can act as causal for, and/or co-aggravating factors of, core, behavioral and cognitive symptoms in ASD. We propose a multi-modal, human subjects and animal models program which encompasses four synergistic projects aimed at characterizing the role of sleep fragmentation and physiology on the core symptoms of ASD. We will examine Sleep EEG, daytime awake, resting EEG, and actigraphy in 150 individuals with ASD, 4 to 17 years, compared to 75 age- and sex-matched Typical Developing (TD) controls and determine the impact of these sleep parameters on core symptoms (Project 1). Using a target engagement approach, we will determine if normalization of sleep is associated with improvements in the core symptoms (Project 2). We will examine if these findings are recapitulated in genetic animal models of ASD (Mice: Project 3; & Zebrafish: Project 4). The evolutionary conservation of Sleep EEG signatures and behavior makes this a powerful translational approach as the same physiological parameters, biological endpoints and behavioral phenotypes can be compared across species, revealing if there is a convergence of the impact of sleep phenotypes across different genetic models of ASD, or alternatively differential pathways from sleep phenotypes to core symptoms. Specific Aim 1: To leverage comparative biology across humans with ASD and controls and complementary genetic animal models of ASD and wild type to examine if multisystem sleep measurements across species a) converge on a common phenotype of sleep fragmentation and architecture in ASD; or b) capture different sub- phenotypes of sleep dysregulation and sleep architecture across species. Specific Aim 2: Examine if a) the sleep phenotypes identified are differentially associated with the core, behavioral and cognitive symptoms of ASD across humans with ASD and complementary genetic animal models of ASD; b) if sleep normalization in humans with ASD and in complementary genetic animal models of ASD, alleviate the core, behavioral and cognitive symptoms of ASD; and c) if these effects are moderated by age and/or sex. Specific Aim 3: Provide research and collaborative opportunities to junior and established researchers new to the field of autism, or established in the field of autism but new to the research emphases of the ACE Center.

我们提议的自闭症卓越中心（ACE）的使命是检查睡眠失调是否是 ASD症状发展和加剧的核心。动物数据表明睡眠是 基本脑结构，神经元发育和突触可塑性的成熟至关重要。 睡眠失调是ASD患者中最繁重的症状之一。晚睡觉， 经常夜间觉醒，睡眠碎片和异常的睡眠数量标志着ASD的睡眠。睡觉 脑电图研究表明，REM睡眠较少，非REM睡眠增加。尽管它在大脑中的核心作用 发展和功能，睡眠障碍通常被视为次要。我们的主要目标 ASD睡眠中心是确定睡眠障碍是否反映了可以充当的融合途径 ASD中核心，行为和认知症状的因果因素和/或共磨碎因素。我们提出了一个 多模式，人类主题和动物模型计划，该计划包括四个协同项目 在表征睡眠破碎和生理学对ASD核心症状的作用时。我们将 检查150名ASD的人，4至17岁的人，检查睡眠脑电图，白天醒来，静息脑电图和精神分裂症 与75个年龄和性别匹配的典型发展（TD）对照相比，确定这些控制的影响 核心症状的睡眠参数（项目1）。使用目标参与方法，我们将确定是否 睡眠的归一化与核心症状的改善有关（项目2）。我们将检查是否 这些发现在ASD的遗传动物模型中概括了（小鼠：项目3；斑马鱼：项目4）。这 进化的睡眠脑力签名和行为使这成为一种强大的翻译方法 作为相同的生理参数，可以比较生物终点和行为表型 整个物种，揭示睡眠表型在不同遗传上的影响是否存在 从睡眠表型到核心症状的ASD模型或不同的途径。 特定目的1：利用ASD和对照和互补的人类的比较生物学 ASD和野生类型的遗传动物模型检查是否跨物种A中的多系统睡眠测量值） 在ASD中融合睡眠破碎和建筑的常见表型；或b）捕获不同的子 - 跨物种的睡眠失调和睡眠结构的表型。具体目标2：检查a）是否 确定的睡眠表型与核心，行为和认知症状有不同的相关性 ASD的ASD与ASD的ASD和互补的遗传动物模型之间的ASD； b）如果睡眠正常化 ASD和ASD互补遗传动物模型的人类，减轻了核心，行为和 ASD的认知症状； c）如果这些影响是按年龄和/或性别调节的。特定目标3：提供 研究和协作机会为初级和成立的自闭症领域的研究人员或 在自闭症领域建立，但是王牌中心的研究重点的新事物。