Shank3 in Autism and sleep disturbances

Shank3 在自闭症和睡眠障碍中的作用

• 批准号: 9767298
• 负责人: Lucia Peixoto
• 金额: $ 20.68万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767298
• 关键词: Address; Affect; Aggressive behavior; Animal Model; Applications Grants; Back; Behavior; Candidate Disease Gene; Complement; Data; Development; Diagnostic; Disease; Drowsiness; Electrophysiology (science); Ensure; Environment; Exhibits; FRAP1 gene; Failure; Family; Foundations; Future; Gene Mutation; Genes; Genetic Determinism; Genetic Transcription; Genomics; Goals; Homeostasis; Hour; Human; Individual; International; K-Series Research Career Programs; Learning; Link; MAP Kinase Gene; Mammals; Medicine; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Molecular Biology; Mutant Strains Mice; Neurobiology; Neurodevelopmental Disorder; Pathway interactions; Patients; Performance; Pharmacology; Phelan-McDermid syndrome; Phenotype; Phosphorylation; Population; Postdoctoral Fellow; Process; Protein Biosynthesis; Quality of life; Rare Diseases; Recovery; Registries; Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Senior Scientist; Severities; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Symptoms; Syndrome; Testing; Time; Training; United States; Western Blotting; Wild Type Mouse; autism spectrum disorder; awake; college; experimental study; falls; genetic manipulation; improved; mTOR inhibition; molecular marker; mutant; neurobehavioral; programs; protein degradation; repetitive behavior; response; sleep behavior; sleep onset; sleep pattern; sleep regulation; social; social communication; success; therapy design; tool; transcriptome sequencing

Project Summary: Understanding sleep problems in the Autism Spectrum through Shank3. Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the US. Several studies have demonstrated that sleep problems occur in ASD at a much higher rate than in typical development. Sleep problems predict the severity of ASD core diagnostic symptoms (e.g., repetitive behaviors and social/communication deficits) as well as other associated problems (e.g., tantrums and aggression). Therefore, understanding the mechanism behind why individuals with ASD have difficulties with sleep holds great promise toward designing interventions to improve quality of life of patients and their families. Study of monogenic syndromes with a high rate of ASD as well as animal models carrying single gene mutations has proven valuable to understand mechanisms underlying ASD. In this context, in my preliminary studies I investigated the role of Shank3, a high confidence ASD gene candidate, in the regulation of sleep. Complete deletion of Shank3 leads Phelan McDermid Syndrome (PMS), a rare disease strongly associated with ASD. Using data on sleep habits obtained from the PMS International Registry, I found that problems with sleep onset are present in >50% of patients. I then performed electrophysiological recordings in Shank3 mutant mice, and found that mutants sleep less than wild-type (WT) mice following sleep deprivation (SD).!Given what we know about how sleep need is regulated, these results can be explained through two alternative hypotheses: 1) Shank3 mutants do not accumulate increased sleep need after SD (they are not as sleepy) or 2) Shank3 mutants do accumulate increased sleep need after SD but have difficulties transitioning from wake to sleep (they are unable to fall asleep when sleepy). The goal of this K01 Career Development award is to obtain additional training and perform additional experiments to differentiate between these two alternative hypotheses as a starting point to an independent line of research. In specific aim 1, I will pursue additional training to investigate the role of Shank3 in regulating sleep need using electrophysiology. In specific aim 2, I will build on previous studies I conducted as a postdoctoral fellow and as a PI to investigate the biomolecular mechanism linking Shank3 with disturbed sleep. My mentoring team includes Dr. John Roll, the Vice- Dean of Research of the College of Medicine, as well as senior scientists from the world-renowned Sleep and Performance Research Center (SPRC) at WSU: Dr. Hans Van Donguen, Dr, Greg Belenky and Dr. Jonathan Wisor. They will ensure the success of my training plan with the environment and resources provided by the College of Medicine and the SPRC at WSU. The proposed training will complement my prior expertise in behavior, molecular biology and genomics to help me establish a research program as an independent investigator that will focus on using genomic and candidate gene approaches to understand the interaction between genes and sleep in ASD.

项目摘要：通过Shank3了解自闭症谱系中的睡眠问题。 自闭症谱系障碍（ASD）是美国最普遍的神经发育障碍。一些 研究表明，睡眠问题以ASD的速度比典型的速度高得多 发展。睡眠问题预测了ASD核心诊断症状的严重程度（例如，重复行为 和社会/沟通缺陷）以及其他相关问题（例如发脾气和侵略性）。 因此，了解为什么ASD患者在睡眠困难中遇到困难的原因背后的机制 设计干预措施以改善患者及其家人的生活质量的巨大希望。研究 具有高的ASD率以及携带单基因突变的动物模型的单基因综合征具有 被证明是了解ASD潜在机制的价值。在这种情况下，在我的初步研究中 调查了ASD基因候选者的高信任Shank3在睡眠调节中的作用。完全的 Shank3的缺失导致Phelan McDermid综合征（PMS），这是一种与ASD密切相关的罕见疾病。 使用从PMS国际注册表获得的睡眠习惯的数据，我发现睡眠问题 > 50％的患者出现发作。然后，我在shank3突变体中进行了电生理记录 小鼠，发现在睡眠剥夺后的突变体的睡眠小于野生型（wt）小鼠（SD）。！ 我们知道如何调节睡眠需求，可以通过两个替代方案来解释这些结果 假设：1）Shank3突变体在SD后不会积累增加睡眠需求（它们不那么困倦）或 2）Shank3突变体确实会在SD后积累增加的睡眠需求，但很难从唤醒过渡 入睡（他们困倦时无法入睡）。这个K01职业发展奖的目标是 获得额外的培训并执行其他实验以区分这两个替代方案 假设是独立研究线的起点。在特定目标1中，我将追求更多 训练以研究Shank3在使用电生理学调节睡眠需求中的作用。具体 AIM 2，我将基于我作为博士后研究员进行的先前研究，并作为PI进行调查 将shank3与睡眠障碍联系起来的生物分子机制。 我的指导团队包括医学院研究副院长约翰·罗尔（John Roll），以及 WSU的世界知名睡眠和表演研究中心（SPRC）的高级科学家：汉斯博士 Van Donguen，博士，Greg Belenky和Jonathan Wisor博士。他们将确保我的培训计划的成功 WSU医学院和SPRC提供的环境和资源。提议 培训将补充我先前在行为，分子生物学和基因组学方面的专业知识，以帮助我建立一个 作为独立研究者的研究计划，将专注于使用基因组和候选基因 了解基因与ASD睡眠之间的相互作用的方法。

项目成果

Critical periods and Autism Spectrum Disorders, a role for sleep.

• DOI: 10.1016/j.nbscr.2022.100088
• 发表时间: 2023-05
• 期刊: Neurobiology of sleep and circadian rhythms
• 作者: Medina, Elizabeth;Peterson, Sarah;Ford, Kaitlyn;Singletary, Kristan;Peixoto, Lucia
• 通讯作者: Peixoto, Lucia

Shank3 influences mammalian sleep development.

• DOI: 10.1002/jnr.25119
• 发表时间: 2022-12
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Medina, Elizabeth;Schoch, Hannah;Ford, Kaitlyn;Wintler, Taylor;Singletary, Kristan G.;Peixoto, Lucia
• 通讯作者: Peixoto, Lucia