Project 2: Wilkerson

项目2--项目总结 自闭症谱系障碍(ASD)在美国每54名儿童中就有1名发生，通常以听力障碍为特征，如 听力亢进、听觉加工障碍和感音神经性耳聋，以及社交障碍 沟通。神经发育及其疾病生物医学研究卓越中心 支持所需的交叉、创新研究，以促进对独特的 自闭症患者听觉系统的听力障碍和病理生理学及其在社会交流中的作用。 这项研究研究了外周听觉系统在听力障碍发生和发展中的作用 脆性X综合征(FXS)小鼠模型中ASD样行为，FXS是最常见的单基因类型 ASD.我们假设FXS患者的听力障碍部分是由于耳蜗的缺陷和 神经元和非神经元Fmr1表达细胞的功能障碍，包括感觉毛细胞，但也包括其他 内耳中的非感觉细胞。目标1测试挽救听力功能和缓解相关ASD样症的方法 发育中Fmr1基因敲除(KO)小鼠的行为和Aim 2研究其病理生理变化 Fmr1KO单核耳蜗细胞组成及细胞类型特异性基因表达谱的研究 RNA-seq(SnRNA-seq)。我们的发现可以为(1)外周感觉缺陷的作用提供新的证据 在ASD相关症状中，(2)对神经元和非神经元FMRP功能在ASD中的作用的关键新见解 以及(3)测试一种可能挽救听力的基因治疗方法 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患者外周听觉系统紊乱，本研究采用组学方法进行系统定位 复杂的遗传网络。ASD听力差异的基本过程研究 能够确定解决听力差异以及相关语言和社会问题的治疗策略 沟通方面的挑战。此项目的CNDD的关键组件是神经行为的核心 表型鉴定，活体成像，生物信息学，高级生物统计学咨询，还有重要的 用于研究能力和培训的资源，包括职业发展指导和工具 走向独立并成功地获得R01级别的资金，以继续在 ASD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.