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: 10605846
• 负责人: Sarah E. Fitzpatrick
• 金额: $ 3.17万
• 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/10605846
• 关键词: Address; Affect; Affinity Chromatography; Autism Diagnosis; Biological Models; Biological Process; Biological Testing; Brain; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Cycle Regulation; Cell Differentiation process; Cells; Child; Chromatin Remodeling Factor; 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; Individual; Larva; Lead; Learning; Light; Mentors; Mitosis; Mitotic; 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; Work; Zebrafish; autism spectrum disorder; base; brain abnormalities; cell type; clinical phenotype; communication behavior; de novo mutation; helicase; improved; in vitro Model; in vivo; insight; loss of function mutation; migration; mutant; nerve stem cell; neurobiological mechanism; neurodevelopment; neuromechanism; progenitor; protein expression; relating to nervous system; repetitive behavior; risk variant; single-cell RNA sequencing; social skills; stem cell proliferation; synaptogenesis; transcriptome; translatome

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，其特征在于 社交技能、语言和非语言交流以及重复行为方面的障碍。ASD高度 在美国，每44名儿童中就有1名受到影响，并且已经研究了几十年，但是， 导致这种疾病的潜在神经机制还知之甚少。没有生物测试来诊断 ASD早期也没有针对ASD核心症状的治疗方法。鉴定与功能 对高置信度ASD风险基因的分析开始揭示基因的趋同途径， 不同的功能导致ASD。染色体结构域解旋酶DNA结合蛋白8（CHD8）的从头突变 是与自闭症最密切相关的CHD8编码影响细胞周期的染色质修饰剂 通过其在基因表达调控中的作用而进展。细胞周期控制影响神经细胞的 祖细胞（NPC）增殖和分化为神经元，这奠定了基础， 神经发育尽管迄今为止的许多研究已经提高了我们对CHD8功能的认识，但仍存在一些问题。 我们对CHD8突变如何改变细胞周期进程和神经增殖的理解仍然存在关键差距， 以及这些变化背后的分子机制。 为了解决这些缺口，我将使用一个在chd8中具有功能缺失突变的斑马鱼品系。斑马鱼提供 以小鼠或体外不可行的方式研究早期神经发育过程的关键优势 模型受精后约14至96小时（hpf）发生神经增殖和迁移， 获得难以在小鼠中研究的胚胎时间点。这个脊椎动物系统可以让我们直接 在关键时刻研究细胞，转录和回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至关重要。根据我 根据初步数据，我假设CHD8突变导致参与 翻译起始和细胞周期相变，导致细胞周期时间和神经增殖的改变 和分化，这可能最终影响突触发生和回路形成。目标1将研究如何 当CHD8基因突变影响细胞周期时间和NPC增殖与分化的平衡时， 在早期脊椎动物体内神经发育中的作用。目标2将研究的机制变化， 通过研究CHD8突变对蛋白质合成的影响来研究细胞周期进程。 总之，我的研究将使用严格的多层次方法来阐明CHD8在以下方面的作用： 神经发育细胞周期调控和蛋白质合成，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， 严格的科学训练，我的训练计划为我提供了无数的成长机会， 导师追求我的长期目标，成为一个独立的物理学家，科学家。