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

基本信息

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
项目类别：
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

项目摘要

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）是指一组为特征的神经发育状况社交技能，言语和非语言交流以及重复行为的障碍。 ASD是高度的普遍，在美国影响多达四分之一的儿童中有1个，并且已经研究了数十年，但是导致该疾病的潜在神经机制知之甚少。没有生物测试可以诊断 ASD较早或针对ASD核心症状的治疗方法可用。识别和功能高信心ASD风险基因的分析开始揭示融合途径各种功能导致ASD。染色体蛋白酶DNA结合蛋白8（CHD8）中的从头突变（CHD8）与ASD最密切相关。 CHD8编码影响细胞周期的染色质修饰符通过其在基因表达调节中的作用进展。细胞周期控制会影响神经的时间祖细胞（NPC）的增殖和分化为神经元，这为正确的基础奠定了基础神经发育。尽管迄今为止的许多研究都改善了我们对CHD8功能的见解，但仍有在我们对CHD8突变如何改变细胞周期进程和神经增殖的理解中仍然存在关键的差距，当发生这些改变时，这些变化的分子机制。为了解决这些差距，我将使用CHD8中具有功能丧失突变的斑马鱼线。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型号。神经增殖和迁移发生后约14到96小时（HPF），可轻松访问小鼠难以研究的胚胎时间点。这个脊椎动物系统将使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要点，这对于理解CHD8在塑造发展中的大脑方面的功能至关重要。基于我初步数据，我假设CHD8突变导致参与的蛋白质表达降低翻译起始和细胞周期相的转变，导致细胞周期时机和神经增殖发生了变化和分化，这可能最终影响突触发生和电路形成。 AIM 1将调查如何当CHD8中的突变影响细胞周期时机以及NPC增殖和分化的平衡时在体内跨越早期的脊椎动物神经发育。 AIM 2将调查变化的基础机制通过研究CHD8突变对蛋白质合成的影响，细胞周期的进展。我的研究将共同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，这将提高我们对ASD的理解神经生物学。除了在强大的模型系统中学习技术方法外，还将为我提供严格的科学培训，我的培训计划为我提供了许多增长机会指导者追求成为独立医师科学家的长期目标。