Project 2: Wilkerson

项目2 -项目概要 自闭症谱系障碍（ASD）发生在1/54的美国儿童，通常具有听力障碍，如 听觉过敏、听觉处理障碍和感觉神经性听力损失，沿着社交困难 通信神经发育及其障碍生物医学研究卓越中心（CNDD） 支持跨领域的创新研究，以促进对独特的 ASD中听觉系统的听力损伤和病理生理学及其在社会交往中的作用。 本研究旨在研究外周听觉系统在听力障碍发展中的作用， 在脆性X综合征（FXS）小鼠模型中的ASD样行为，FXS是最常见的单基因型自闭症。 自闭症我们假设，FXS患者的听力障碍部分是由于耳蜗缺陷， 神经元和非神经元的Fmr 1表达细胞，包括感觉毛细胞，以及其他 内耳中的非感觉细胞。目的1测试挽救听力功能和减轻相关ASD样的方法 行为在发展中的Fmr 1敲除（KO）小鼠和目的2研究的病理生理变化 在单个核的Fmr 1 KO耳蜗中的细胞组成和细胞类型特异性基因表达模式中 RNA-seq（snRNA-seq）。我们的研究结果可以提供（1）关于外周感觉缺陷的作用的新证据 （2）对神经元与非神经元FMRP功能在ASD相关症状中的作用的重要新见解， 耳蜗发育和听觉功能;（3）测试可能挽救听觉的基因治疗方法 功能和/或减少ASD的沟通相关症状。为了了解基因网络是如何 ASD患者的外周听觉系统失调，本研究采用组学方法进行系统定位 复杂的基因网络。研究导致ASD听力差异的基本过程 可以确定治疗策略，以解决听力差异和相关的语言和社会 沟通挑战。该项目CNDD的关键组成部分是神经行为 表型，体内成像，生物信息学，先进的生物统计咨询，也显着 研究能力和培训资源，包括职业发展辅导和工具， 独立性的进步和获得R 01级资金的成功，以继续在 ASD中听觉系统的病理生理学。

PROJECT 2 – PROJECT SUMMARY Autism spectrum disorder (ASD) occurs in 1 in 54 US children and often features hearing impairments such as hyperacusis, auditory processing disorders and sensorineural hearing loss, along with difficulties in social communication. The Center of Biomedical Research Excellence in Neurodevelopment and its Disorders (CNDD) supports the cross-cutting, innovative research needed to advance fundamental understanding of the unique hearing impairments and pathophysiology of the auditory system in ASD and their role in social communication. This research studies the role of the peripheral auditory system in the development of hearing impairments and ASD-like behaviors in a mouse model of Fragile X Syndrome (FXS), the most common monogenetic type of ASD. We hypothesize that hearing impairments in FXS are due in part to defects in the cochlea and to dysfunction in both neuronal and non-neuronal Fmr1-expressing cells including sensory hair cells, but also other nonsensory cells in the inner ear. Aim 1 tests methods to rescue hearing function and mitigate related ASD-like behaviors in the developing Fmr1 knockout (KO) mouse and Aim 2 investigates the pathophysiological changes in cellular composition and cell type-specific gene expression patterns in the Fmr1 KO cochlea by single nucleus RNA-seq (snRNA-seq). Our findings could provide (1) new evidence about the role of peripheral sensory deficits in ASD-related symptoms, (2) critical new insights into the role of neuronal vs. non-neuronal FMRP functions in cochlear development and auditory function and (3) test a gene therapeutic approach to possibly rescue auditory function and/or reduce communication-related symptoms of ASD. To understand how gene networks in the peripheral auditory system are deregulated in ASD, this research uses omics approaches for systematic mapping of complex genetic networks. Study of the fundamental processes that contribute to hearing differences in ASD could identify therapeutic strategies to resolve hearing differences and related language and social communication challenges. Critical components of the CNDD for this project are cores for neurobehavioral phenotyping, in vivo imaging, and bioinformatics, advanced biostatistical consulting, and also significant resources for research capacity and training including career development mentorship and tools for advancement to independence and success in obtaining R01-level funding to continue research in the pathophysiology of the auditory system in ASD.