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) 是美国最常见的神经发育障碍。一些 研究表明，自闭症谱系障碍 (ASD) 患者出现睡眠问题的几率比典型患者高得多 发展。睡眠问题可以预测 ASD 核心诊断症状的严重程度（例如，重复行为） 和社交/沟通缺陷）以及其他相关问题（例如发脾气和攻击性）。 因此，了解自闭症谱系障碍患者睡眠困难背后的机制 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 自闭症谱系障碍（ASD）发生率高的单基因综合征以及携带单基因突变的动物模型 事实证明对于理解 ASD 的潜在机制很有价值。在此背景下，我在前期研究中 研究了 Shank3（一种高度可信的 ASD 候选基因）在睡眠调节中的作用。完全的 Shank3 缺失会导致费兰·麦克德米德综合症 (PMS)，这是一种与自闭症谱系障碍 (ASD) 密切相关的罕见疾病。 使用从 PMS 国际登记处获得的睡眠习惯数据，我发现睡眠问题 >50% 的患者出现这种情况。然后我在 Shank3 突变体中进行了电生理记录 小鼠，并发现在睡眠剥夺 (SD) 后，突变体小鼠的睡眠时间比野生型 (WT) 小鼠少。！ 我们知道睡眠需求是如何调节的，这些结果可以通过两种替代方法来解释 假设：1) Shank3 突变体在 SD 后不会累积增加的睡眠需求（它们不那么困）或 2) Shank3突变体在SD后确实积累了增加的睡眠需求，但从清醒状态过渡有困难 睡觉（困时无法入睡）。 K01 职业发展奖的目标是 获得额外的培训并进行额外的实验来区分这两种替代方案 假设作为独立研究的起点。在具体目标 1 中，我将追求额外的目标 使用电生理学研究 Shank3 在调节睡眠需求中的作用的培训。具体来说 目标 2，我将在我之前作为博士后研究员和 PI 进行的研究的基础上，调查 Shank3 与睡眠障碍相关的生物分子机制。 我的导师团队包括医学院研究副院长 John Roll 博士，以及 来自世界著名的华盛顿州立大学睡眠与表现研究中心 (SPRC) 的资深科学家：Hans 博士 Van Donguen、Greg Belenky 博士和 Jonathan Wisor 博士。他们将确保我的培训计划取得成功 WSU 医学院和 SPRC 提供的环境和资源。拟议的 培训将补充我之前在行为、分子生物学和基因组学方面的专业知识，帮助我建立一个 作为独立研究者的研究计划将重点关注使用基因组和候选基因 了解自闭症谱系障碍中基因与睡眠之间相互作用的方法。

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