Shank3 in Autism and sleep disturbances

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。几个 研究表明，自闭症患者出现睡眠问题的比率比典型自闭症患者要高得多。 发展。睡眠问题预测ASD核心诊断症状(例如，重复行为)的严重程度 和社交/沟通障碍)以及其他相关问题(例如，发脾气和攻击)。 因此，了解ASD患者睡眠障碍背后的机制 在设计干预措施以提高患者及其家人的生活质量方面有着巨大的希望。的研究 具有高ASD发生率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，这对了解ASD的潜在机制是有价值的。在这方面，在我的初步研究中，我 研究了高度自信的ASD基因候选基因Shank3在睡眠调节中的作用。完成 Shank3基因缺失导致费兰-麦克德米德综合征(PMS)，这是一种与ASD密切相关的罕见疾病。 使用从经前综合症国际注册中心获得的睡眠习惯数据，我发现睡眠问题 50%的患者起病。然后，我对Shank3突变体进行了电生理记录 小鼠，并发现在睡眠剥夺(SD)后，突变型小鼠比野生型(WT)小鼠睡眠更少。 我们知道睡眠需求是如何被调节的，这些结果可以通过两种选择来解释 假设：1)Shank3突变体在SD后没有积累更多的睡眠需求(他们不那么困)或 2)Shank3突变体在SD后确实积累了更多的睡眠需求，但在从清醒状态过渡方面存在困难 入睡(他们困了也睡不着)。K01职业发展奖的目标是 获取其他培训并执行其他实验，以区分这两个备选方案 假设作为一条独立研究路线的起点。在具体目标1中，我将追求更多 利用电生理学研究Shank3在调节睡眠中的作用。具体而言 目标2，我将在我以前作为博士后研究员和私人投资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。 我的指导团队包括医学院研究副院长约翰·罗尔博士，以及 威斯康星州立大学世界著名睡眠与性能研究中心资深科学家：汉斯博士 Van Donguen，Greg Belenky博士和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。建议数 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 作为独立调查者的研究计划，将专注于使用基因组和候选基因 了解ASD中基因和睡眠之间相互作用的方法。

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.