Relating interindividual differences in cerebral organoid models to longitudinal infant brain growth and cognitive development

将大脑类器官模型的个体差异与婴儿大脑纵向生长和认知发展联系起来

• 批准号: 10598515
• 负责人: Madison Rose Glass
• 金额: $ 2.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598515
• 关键词: Adaptive Behaviors; Age Months; Area; Autism diagnostic; Behavior; Behavioral; Biological Models; Brain; Brain imaging; Cell Line; Cell Reprogramming; Cells; Cerebrum; Child; Clinical; Clone Cells; Cognitive; Collaborations; Communication; Data; Data Set; Development; Disease; Family history of; Gene Expression; Gene Structure; Growth; Growth and Development function; Human; In Vitro; Individual; Individual Differences; Infant; Infant Development; Lead; Learning; MRI Scans; Magnetic Resonance Imaging; Measurement; Mentorship; Modeling; Molecular; Nature; Neurodevelopmental Disorder; Neuroepithelial; Neuroglia; Neurons; North Carolina; Organoids; Outcome; Participant; Patients; Phenotype; Population; Production; Proliferating; Protocols documentation; Radial; Reproducibility; Research Personnel; Risk; Siblings; Structure; Surface; Technology; Testing; Time; Tissues; Training; Universities; Variant; autism spectrum disorder; behavior measurement; brain magnetic resonance imaging; brain size; career networking; cell type; cognitive ability; cognitive development; cohort; donor stem cell; endophenotype; excitatory neuron; experimental study; fetal; high risk; human model; imaging study; in vitro Model; in vivo; induced pluripotent stem cell; insight; interest; neurodevelopment; neurogenesis; neuropsychiatric disorder; postnatal; predictive modeling; progenitor; single-cell RNA sequencing; skills; trait; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT Induced pluripotent stem cells (iPSCs) and human cerebral organoids are poised to provide insight into how brain development changes in individuals with neurodevelopmental disorders. Though the molecular fidelity of cortical organoids have been assessed relative to the primary fetal brain reference datasets, it is unknown how well cortical organoid phenotypes predict inter-individual differences in postnatal longitudinal brain growth. Identifying what in vitro phenotypes are related to in vivo traits will be useful for interpreting experiments implementing organoids to understand mechanisms of neurodevelopment disorders. To test this relationship, it is necessary to derive a population of iPSC lines from well-characterized individuals. This proposal uses iPSC- derived cerebral organoids from participants in the Infant Brain Imaging Study (IBIS) to test the relationship between organoid neuroepithelial bud structure and gene expression phenotypes to in vivo brain development and cognitive behavioral measurements. Specifically, this proposal uses 17 iPSC lines generated from 5 participants without a family history of neuropsychiatric disorders, 9 participants who had a sibling with ASD, and 3 participants with ASD, each with at least 2 brain MRI scans at 6, 12 and/or 24 months of age. All participants have Mullens Scale of Early Learning, Vineland Adaptive Behavior and Autism Diagnostic Observation Scale score at 24 months of age. 3 clones of each iPSC line were generated. To identify inter- individual differences between iPSC donors and within iPSC clones from the same individual, we will assess single cell gene expression and organoid structure across the differentiation. Single cell RNA sequencing will be performed after neuroepithelial buds form (14 days post differentiation) and neuronal maturation (84 days post differentiation). Intact organoid immunolabeling will be completed at these time points and earlier in neurogenesis (56 days post differentiation). When completed, this project will identify the strengths and limitations of cerebral organoids as reproducible, predictive models of human cortical development. This proposal seeks to leverage the rigorous coursework, mentorships, networks and technical training available at the University of North Carolina at Chapel Hill and through IBIS collaborators. By completing this proposal, the applicant will have the appropriate technical training and communication skills to become an independent investigator with a strong professional network in the field of neurodevelopment.

项目概要/摘要 诱导多能干细胞 (iPSC) 和人脑类器官有望帮助我们深入了解如何 患有神经发育障碍的个体的大脑发育发生变化。尽管分子保真度 皮质类器官已相对于初级胎儿大脑参考数据集进行了评估，目前尚不清楚如何 皮质类器官表型可以很好地预测出生后纵向大脑生长的个体间差异。 确定哪些体外表型与体内特征相关将有助于解释实验 实施类器官来了解神经发育障碍的机制。为了检验这种关系， 从特征良好的个体中获得 iPSC 系群体是必要的。该提案使用 iPSC- 从婴儿脑成像研究 (IBIS) 参与者中提取大脑类器官来测试这种关系 类器官神经上皮芽结构和基因表达表型与体内大脑发育之间的关系 和认知行为测量。具体来说，该提案使用 5 个 iPSC 系生成的 17 个 iPSC 系。 没有神经精神疾病家族史的参与者，有兄弟姐妹患有自闭症谱系障碍的 9 名参与者， 3 名患有 ASD 的参与者，每人在 6、12 和/或 24 个月大时至少接受过 2 次脑部 MRI 扫描。全部 参与者有 Mullens 早期学习量表、Vineland 适应行为和自闭症诊断 24 月龄时的观察量表评分。每个 iPSC 系生成 3 个克隆。为了识别间 iPSC 供体之间以及同一个体的 iPSC 克隆内的个体差异，我们将评估 单细胞基因表达和分化过程中的类器官结构。单细胞 RNA 测序将 在神经上皮芽形成（分化后 14 天）和神经元成熟（84 天）后进行 后微分）。完整的类器官免疫标记将在这些时间点和更早的时间点完成 神经发生（分化后 56 天）。完成后，该项目将确定优势和 大脑类器官作为人类皮质发育的可重复、预测模型的局限性。这 该提案旨在利用严格的课程、指导、网络和技术培训 北卡罗来纳大学教堂山分校和 IBIS 合作者。通过完成本提案， 申请人将接受适当的技术培训和沟通技巧，成为独立的 研究员在神经发育领域拥有强大的专业网络。