The Role of the ASD Risk Gene CHD8 in Neural Development

ASD 风险基因 CHD8 在神经发育中的作用

• 批准号: 10705080
• 负责人: Sarah E. Fitzpatrick
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2026-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705080
• 关键词: Address; Affect; Affinity Chromatography; Autism Diagnosis; Behavior; Biological Models; Biological Process; Biological Testing; Brain; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Cycle Regulation; Cell Differentiation process; Cell Proliferation; Cell Separation; Cells; Child; Chromatin Remodeling Factor; Communication; Confocal Microscopy; Coupled; DNA-Binding Proteins; Data; Development; Diagnosis; Disease; Embryo; Equilibrium; Fertilization; Flow Cytometry; Fluorescence; Foundations; Frameshift Mutation; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic Transcription; Goals; Growth; Hour; Image; Impairment; Larva; Lead; Learning; Mentors; Mitosis; Modeling; Molecular; Mus; Mutation; Neurobiology; Neurodevelopmental Disorder; Neurons; Nonverbal Communication; Orthologous Gene; Pathway interactions; Patients; Pharmacological Treatment; Phase; Phase Transition; Physicians; Ploidies; Prevalence; Process; Proliferating; Protein Biosynthesis; Proteins; Reporter; Research; Ribosomes; Role; Scientist; Shapes; Symptoms; Synapses; System; Time; Training; Transcript; Transgenic Organisms; Translating; Translation Initiation; Translations; Ubiquitination; United States; Visualization; Work; Zebrafish; autism spectrum disorder; brain abnormalities; cell type; clinical phenotype; communication behavior; de novo mutation; helicase; improved; in vitro Model; in vivo; individuals with autism spectrum disorder; insight; loss of function mutation; migration; mutant; nerve stem cell; neural; neurobiological mechanism; neurodevelopment; neuromechanism; postmitotic; progenitor; protein expression; repetitive behavior; risk variant; single-cell RNA sequencing; social skills; stem cell proliferation; synaptogenesis; transcriptome; translatome; verbal

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental conditions characterized by impairments in social skills, verbal and nonverbal communication, and repetitive behaviors. ASD is highly prevalent, affecting up to 1 in 44 children in the United States and has been studied for decades, yet the underlying neural mechanisms that lead to the disorder are poorly understood. No biological tests to diagnose ASD earlier nor treatments targeting the core symptoms of ASD are available. Identification and functional analyses of high-confidence ASD risk genes are beginning to uncover convergent pathways by which genes with diverse functions lead to ASD. De novo mutations in Chromodomain Helicase DNA Binding Protein 8 (CHD8) are among the most strongly associated with ASD. CHD8 encodes a chromatin modifier that affects cell cycle progression through its role in gene expression regulation. Cell cycle control affects the timing of neural progenitor cell (NPC) proliferation and differentiation into neurons, which lays the foundation for proper neurodevelopment. Although numerous studies to date have improved our insight into CHD8 function, there are still critical gaps in our understanding of how CHD8 mutation alters cell cycle progression and neural proliferation, when these alterations take place, and the molecular mechanisms underlying these changes. To address these gaps, I will use a zebrafish line with a loss-of-function mutation in chd8. Zebrafish provide key advantages for studying early neurodevelopment processes in ways not feasible with mouse or in vitro models. Neural proliferation and migration take place from ~14 to 96 hours post-fertilization (hpf), providing easy access to embryonic timepoints that are difficult to study in mice. This vertebrate system will allow us to directly study fundamental neurodevelopmental processes at cellular, transcriptional, and circuit levels at critical time points, which is essential for understanding the function of CHD8 in shaping the developing brain. Based on my preliminary data, I hypothesize that CHD8 mutation causes decreased expression of proteins involved in translation initiation and cell cycle phase transitions, resulting in altered cell cycle timing and neural proliferation and differentiation, which may ultimately affect synaptogenesis and circuit formation. Aim 1 will investigate how and when mutations in CHD8 affect cell cycle timing and the balance of NPC proliferation and differentiation across early vertebrate neurodevelopment in vivo. Aim 2 will investigate the mechanisms underlying changes in cell cycle progression by investigating the impact of CHD8 mutations on protein synthesis. Together, my research will use rigorous multi-level approaches to elucidate the role of CHD8 in neurodevelopmental cell cycle regulation and protein synthesis, which will advance our understanding of ASD neurobiology. In addition to learning technical approaches in a powerful model system that will provide me with rigorous scientific training, my training plan affords me numerous growth opportunities with the support of superb mentors to pursue my long-term goal of becoming an independent physician-scientist.

自闭症谱系障碍(ASD)是指一组神经发育状况，其特征是 社交技能、言语和非言语交流以及重复行为方面的障碍。ASD是高度 在美国，每44个儿童中就有一个受到影响，几十年来一直被研究，然而 导致这种疾病的潜在神经机制还知之甚少。没有生物测试可供诊断 ASD早期也没有针对ASD核心症状的治疗方法。识别性和功能性 对高置信度ASD风险基因的分析开始揭示基因与 不同的功能导致ASD。染色体解旋酶DNA结合蛋白8(CHD8)的新基因突变 是与ASD关系最密切的。CHD8编码一种影响细胞周期的染色质修饰物 通过其在基因表达调控中的作用而取得进展。细胞周期调控影响神经发生的时间 祖细胞(NPC)的增殖和分化为神经元奠定了良好的基础 神经发育。尽管到目前为止的大量研究提高了我们对CHD8功能的洞察力，但有 在我们对CHD8突变如何改变细胞周期进展和神经增殖的理解中仍然存在关键差距， 当这些变化发生时，以及这些变化背后的分子机制。 为了解决这些差距，我将使用CHD8功能缺失突变的斑马鱼品系。斑马鱼提供 用小鼠或体外不可行的方法研究早期神经发育过程的主要优势 模特们。神经的增殖和迁移发生在受精后约14到96小时(HPF)，为 获得在小鼠身上很难研究的胚胎时间点。这个脊椎动物系统将允许我们直接 在关键时间研究细胞、转录和电路水平的基本神经发育过程 这对于理解CHD8在塑造发育中的大脑中的功能是必不可少的。基于我的 初步数据显示，我推测CHD8基因突变导致相关蛋白表达减少 翻译启动和细胞周期相变，导致细胞周期时序改变和神经增殖 和分化，这可能最终影响突触发生和回路形成。AIM 1将调查如何 当CHD8基因突变影响细胞周期时间和鼻咽癌增殖与分化的平衡时 在活体内早期脊椎动物的神经发育。目标2将调查潜在的变化机制 通过研究CHD8突变对蛋白质合成的影响来研究细胞周期的进展。 总之，我的研究将使用严格的多层次方法来阐明CHD8在 神经发育、细胞周期调节和蛋白质合成，这将促进我们对ASD的理解 神经生物学。除了在一个强大的模型系统中学习技术方法外，它还将为我提供 严谨的科学训练，我的训练计划在卓越的支持下为我提供了无数的成长机会 我的长期目标是成为一名独立的内科医生和科学家。