Project 2: Wilkerson

项目2：威尔克森

• 批准号: 10556543
• 负责人: Brent Allen Wilkerson
• 金额: $ 21.89万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556543
• 关键词: Acoustics; Address; Age; Animal Model; Anxiety; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Auditory system; Behavior; Behavioral; Bioinformatics; Biometry; Blood Vessels; Candidate Disease Gene; Cells; Centers for Disease Control and Prevention (U.S.); Centers of Research Excellence; Characteristics; Child; Cochlea; Code; Communication; Complex; Craniofacial Abnormalities; Data; Data Set; Defect; Development; Disease; Epithelial Cells; Etiology; FMR1; FMRP; Fibroblasts; Flatfoot; Fragile X Syndrome; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profile; Generations; Genetic; Genotype; Goals; Hair Cells; Hearing; Hearing problem; Heterozygote; Hyperactivity; Hyperacusis; Immune; Impaired cognition; Interdisciplinary Study; Knock-out; Knockout Mice; Labyrinth; Language; Language Delays; Lateral; Macrophage; Maps; Measurable; Mediating; Mentors; Mentorship; Mesenchymal; Methods; Molecular; Mus; Neonatal; Neuroglia; Neurons; Pathogenesis; Pathway Analysis; Peripheral; Phenotype; Process; RNA; Regulation; Research; Resources; Risk Factors; Role; Seizures; Sensorineural Hearing Loss; Sensory; Sensory Hair; Startle Reaction; Stria Vascularis; Study models; Supporting Cell; Symptoms; Testing; Testis; Therapeutic; Therapeutic Intervention; Tissues; Training; Ultrasonics; Viral; audiogenic seizure; autism spectrum disorder; career development; cell type; cochlear development; gene network; hearing impairment; in vivo imaging; inner ear development; innovation; insight; malformation; mouse model; multidisciplinary; neural; neurobehavioral; neurodevelopment; preference; repetitive behavior; research study; restoration; risk variant; single nucleus RNA-sequencing; single-cell RNA sequencing; social; social communication; sound; success; synaptogenesis; therapeutic gene; tool; transcriptomics; vector control; vocalization; young adult

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.

项目 2 – 项目摘要 自闭症谱系障碍 (ASD) 发生在美国五分之一的儿童中，通常具有听力障碍，例如 听觉过敏、听觉处理障碍和感音神经性听力损失，以及社交困难 神经发育及其疾病生物医学卓越研究中心 (CNDD) 支持跨领域的创新研究，以促进对独特的基本理解 自闭症谱系障碍（ASD）中的听力障碍和听觉系统的病理生理学及其在社交沟通中的作用。 这项研究研究了周围听觉系统在听力障碍发展中的作用和 脆性 X 综合征 (FXS) 小鼠模型中的 ASD 样行为，FXS 是最常见的单基因遗传类型 我们探讨了 FXS 患者的听力障碍部分是由于耳蜗缺陷造成的。 神经元和非神经元 Fmr1 表达细胞（包括感觉毛细胞）以及其他细胞的功能障碍 目标 1 测试挽救听力功能并减轻相关自闭症谱系障碍的方法。 Fmr1 敲除 (KO) 小鼠的行为发展和 Aim 2 研究病理生理变化 单核 Fmr1 KO 耳蜗的细胞组成和细胞类型特异性基因表达模式 RNA-seq (snRNA-seq)。我们的研究结果可以提供 (1) 关于外周感觉缺陷作用的新证据。 在 ASD 相关症状中，(2) 关于神经与非神经元 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，以及（3）测试可能挽救听觉的基因治疗方法 了解基因网络在自闭症谱系障碍中的功能和/或减少与交流相关的症状。 自闭症谱系障碍患者的外周听觉系统失调，本研究使用组学方法进行系统绘图 复杂遗传网络的研究导致自闭症谱系障碍听力差异的基本过程。 可以确定治疗策略来解决听力差异以及相关的语言和社交问题 该项目 CNDD 的关键组成部分是神经行为的核心。 表型分析、体内成像和生物信息学、高级生物统计咨询以及重要的 研究能力和培训资源，包括职业发展指导和工具 取得独立并成功获得 R01 级资金以继续研究 ASD 听觉系统的病理生理学。