Understanding the interaction between sleep and SHANK3/B-catenin signaling in Autism

了解自闭症中睡眠与 SHANK3/B-catenin 信号传导之间的相互作用

• 批准号: 10627198
• 负责人: Lucia Peixoto
• 金额: $ 49.79万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10627198
• 关键词: Affect; Animals; Architecture; Attention; Binding; Brain; Brain region; C-terminal; Candidate Disease Gene; Caregivers; Cell Nucleus; Chromatin; Chronic; Circadian Rhythms; Cognition; Development; Developmental Process; Diagnosis; Disease; Disease model; Drowsiness; EP300 gene; Emotional; Equilibrium; Etiology; Family; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Glutamates; Hippocampus (Brain); Human; Impairment; In Vitro; Individual; Intervention; Lead; Length; Link; Memory; Modeling; Multiomic Data; Mus; Mutant Strains Mice; Mutation; Neurons; Nuclear; Nuclear Protein; Patients; Pharmacology; Phelan-McDermid syndrome; Phenotype; Positioning Attribute; Prefrontal Cortex; Problem behavior; Process; Protein Isoforms; Proteomics; Public Health; Quality of life; Resolution; Rodent; Severities; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleeplessness; Small Nuclear RNA; Surveys; Symptoms; Synapses; Syndrome; Testing; Tissues; Validation; Wild Animals; autism spectrum disorder; base; beta catenin; chromatin remodeling; emotion regulation; experience; falls; improved; individuals with autism spectrum disorder; insight; mouse model; mutant; recruit; response; sleep abnormalities; sleep onset; targeted treatment; transcription factor; treatment group

PROJECT SUMMARY Sleep problems occur at a higher rate in Autism Spectrum Disorder (ASD) than in typical development. Problems falling asleep predict severity of ASD core symptoms and associated problem behaviors, and lead to chronic sleep deprivation (SD). Understanding the effects of sleep deprivation is important because it adversely affects cognition, attention and emotional regulation. Nonetheless, little is known about the mechanisms responsible for abnormal sleep or the consequences of chronic sleep loss in ASD. Identifying these mechanisms may lead to new interventions that will improve quality of life of patients and their families. The study of genetic syndromes with high rate of ASD diagnosis has provided important clues into mechanisms. One such syndrome is Phelan McDermid Syndrome (PMS), characterized by deletions in the SHANK3 gene. Mutations in SHANK3 are also often found in patients with idiopathic ASD. We previously showed that the ASD sleep phenotype is recapitulated in mice with a C-terminal deletion in Shank3 (Shank3∆C), which struggle to fall asleep despite being sleepy (i.e. after SD). We also showed that SD induces greater number of differences in gene expression in Shank3∆C animals than WT. Therefore, we hypothesize that Shank3∆C animals display an abnormal transcriptional response to SD. The objective of this proposal is to identify the mechanisms that underlie the abnormal response to SD in ASD, using Shank3 mutant mice as a model. Our preliminary studies show that SD increases the nuclear localization of full-length SHANK3a, an isoform that is absent in Shank3∆C animals and thought to be primarily synaptic. SHANK3 binds b-catenin. Translocation of β-catenin into the nucleus regulates transcription through chromatin remodeling and is key to many developmental processes. Our preliminary studies show that SD produces changes in chromatin topology in glutamatergic neurons, and that some of these changes do not take place in Shank3∆C animals. Therefore, our central hypothesis is that SD changes chromatin topology and gene expression by increasing nuclear SHANK3a and b-catenin and that the absence of SHANK3a in Shank3∆C interferes with this process. To test our hypothesis, in Aim 1, we will first determine the effects of SD in SHANK3a/b-catenin synaptic-nuclear signaling. Then, in Aim 2, we will determine the effect of SD in SHANK3-dependent chromatin topology and transcription at single-nuclear resolution. We will examine two brain regions important to ASD and impacted by sleep loss: pre-frontal cortex and hippocampus. We will subsequently test candidates prioritized through omic studies for their ability to influence sleep. Completion of these aims will allow us to determine how sleep interacts with SHANK3 and β-catenin to regulate chromatin and gene expression.

项目概要 自闭症谱系障碍 (ASD) 患者出现睡眠问题的比例高于典型患者 入睡问题可预测 ASD 核心症状及相关症状的严重程度。 问题行为，并导致慢性睡眠不足 (SD)。 剥夺很重要，因为它会对认知、注意力和情绪调节产生不利影响。 然而，对于睡眠异常或睡眠异常的机制知之甚少。 自闭症谱系障碍中慢性睡眠不足的后果可能会导致新的发现。 干预措施将改善患者及其家人的生活质量。 自闭症谱系障碍 (ASD) 诊断率高的综合征为了解此类机制提供了重要线索。 综合征是费兰·麦克德米德综合征 (PMS)，其特征是 SHANK3 基因缺失。 SHANK3 突变也常见于特发性自闭症谱系障碍 (ASD) 患者中。 Shank3 C 端缺失的小鼠重现了 ASD 睡眠表型 (Shank3ΔC)，尽管很困但仍难以入睡（即 SD 之后）。 与 WT 相比，Shank3ΔC 动物的基因表达存在更多差异。 我们追踪 Shank3ΔC 动物对 SD 表现出异常的转录反应。 该提案的目的是确定异常反应背后的机制 我们的初步研究表明，自闭症谱系障碍（ASD）中的SD。 增加全长 SHANK3a 的核定位，这是 Shank3ΔC 中不存在的同种型 SHANK3 与 β-连环蛋白易位有关。 进入细胞核通过染色质重塑调节转录，是许多疾病的关键 我们的初步研究表明，SD 会导致染色质发生变化。 谷氨酸能神经元的拓扑结构，并且其中一些变化不会发生在 Shank3ΔC 中 因此，我们的中心假设是 SD 改变了染色质拓扑和基因。 通过增加核 SHANK3a 和 b-连环蛋白的表达以及 SHANK3a 的缺失 Shank3ΔC 会干扰这一过程。为了检验我们的假设，在目标 1 中，我们将首先确定 SD 对 SHANK3a/b-catenin 突触核信号传导的影响 然后，在目标 2 中，我们将确定 SD 在单核分辨率下对 SHANK3 依赖性染色质拓扑和转录的影响。 我们将检查对自闭症谱系障碍很重要且受睡眠不足影响的两个大脑区域：前额皮质 我们随后将测试通过组学研究优先排序的候选人。 影响睡眠的能力将使我们能够确定睡眠如何相互作用。 SHANK3 和 β-catenin 调节染色质和基因表达。