IBIS-iPSC: Organoid modeling of cortical surface area hyperexpansion in autism spectrum disorder

IBIS-iPSC：自闭症谱系障碍皮质表面积过度扩张的类器官建模

基本信息

批准号：
10656866
负责人：
Jason Louis Stein
金额：
$ 86万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656866
关键词：
Age Months Area Behavior Behavior assessment Behavioral Biological Biological Models Biological Process Blood Brain Brain imaging Cell Cycle Cell Line Cells Clinical Control Groups Development Diagnosis Diagnostic Disease Exhibits Family Gene Expression Generations Genotype Growth In Vitro Individual Individual Differences Infant Life Light Measurement Measures Microscopy Modeling Molecular Molecular Profiling Neocortex Neurons Organoids Outcome Participant Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Phenotype Play Population Proliferating Reporting Resources Risk Role Sampling Sampling Studies School-Age Population Siblings Structure Surface Symptoms System Time Tissues Validation Variant autism spectrum disorder behavior measurement brain overgrowth brain size brain volume cell behavior cell type cognitive ability cohort high risk imaging study in vivo in vivo Model individual variation individuals with autism spectrum disorder induced pluripotent stem cell infancy insight inter-individual variation neocortical nerve stem cell neurodevelopment neurogenesis neuroimaging personalized medicine phenotypic data postnatal proband serial imaging single-cell RNA sequencing therapeutic target

项目摘要

Project Summary/Abstract Many individuals with monogenic and idiopathic forms of autism spectrum disorder (ASD) exhibit brain enlargement early in life. However, the underlying cellular and molecular mechanisms leading to early brain overgrowth in ASD are unknown. To identify the mechanisms leading to brain overgrowth, we will use an appropriate model system, iPSC-derived organoids, from a well-powered, deeply phenotyped cohort with multiple control groups, the Infant Brain Imaging Study (IBIS). IBIS is the largest longitudinal neuroimaging study of infants (>250 participants) at high familial risk for autism by virtue of having an older sibling/proband with ASD. Importantly, IBIS participants have previously undergone longitudinal neuroimaging at multiple time points in infancy (between 6-24 months of age) and school age, extensive behavioral assessments at these time points, as well as rare and common variant genotyping. The extensive phenotypic data generated in this cohort make it an ideal population from which to generate iPSC-derived organoid models and relate in vitro phenotypes to in vivo brain growth and behavioral trajectories. Our study also represents a unique opportunity to evaluate how well organoid phenotypes model the in vivo brain growth trajectories of the individual from whom they were derived. In this proposal, we will derive and validate iPSCs from blood for participants from high risk families who developed ASD (HR+), high risk participants who did not develop ASD (HR-), and low risk individuals without ASD (LR-) totaling 99 participants. We will differentiate the iPSC lines to cortical organoids to model inter- individual differences in brain development. We will use single cell (sc)RNA-seq to identify cell types, cell cycle states, and differentiation trajectories in each participant-derived organoid across two time points modeling the period of cortical neurogenesis, totaling 2.38M sequenced cells. We will validate cell type counts and states using tissue clearing followed by lightsheet microscopy of the cortical organoids. We will identify cell types, fate decisions, and cell cycle states that correlate with both cross-sectional and longitudinal cortical surface area growth and ASD symptoms and cognitive ability over time. Leveraging this unique, deeply characterized clinical cohort, we will determine both the in vivo relevance of cortical organoids and the cellular and molecular mechanisms underlying brain overgrowth in ASD.

项目概要/摘要许多患有单基因和特发性自闭症谱系障碍 (ASD) 的个体表现出大脑生命早期的扩大。然而，导致早期大脑发育的潜在细胞和分子机制 ASD 的过度生长尚不清楚。为了确定导致大脑过度生长的机制，我们将使用适当的模型系统，iPSC 衍生的类器官，来自功能强大、深度表型的队列多个对照组，婴儿脑成像研究（IBIS）。 IBIS 是最大的纵向神经影像研究因有患有自闭症谱系障碍的年长兄弟姐妹/先证者而处于自闭症高家族风险的婴儿（>250 名参与者）。重要的是，IBIS 参与者之前曾在多个时间点接受过纵向神经影像检查婴儿期（6-24 个月大）和学龄期，在这些时间点进行广泛的行为评估，以及罕见和常见变异基因分型。该队列中产生的广泛表型数据使其生成 iPSC 衍生类器官模型并将体外表型与体内相关联的理想群体体内大脑生长和行为轨迹。我们的研究还提供了一个独特的机会来评估如何良好的类器官表型模拟了它们所属个体的体内大脑生长轨迹衍生的。在本提案中，我们将为来自高风险家庭的参与者从血液中获取并验证 iPSC。已发展为自闭症谱系障碍 (HR+)、未发展为自闭症谱系障碍的高风险参与者 (HR-) 以及未发展为自闭症谱系障碍的低风险个体 ASD (LR-) 共有 99 名参与者。我们将区分 iPSC 系和皮质类器官，以模拟细胞间的关系大脑发育的个体差异。我们将使用单细胞 (sc)RNA-seq 来识别细胞类型、细胞周期每个参与者衍生的类器官在两个时间点建模的状态和分化轨迹皮质神经发生期，总计2.38M已测序细胞。我们将验证细胞类型计数和状态使用组织透明化，然后对皮质类器官进行光片显微镜检查。我们将识别细胞类型、命运与横截面和纵向皮质表面积相关的决策和细胞周期状态随着时间的推移，生长、自闭症谱系障碍症状和认知能力。利用这种独特的、具有深刻特征的临床队列中，我们将确定皮质类器官的体内相关性以及细胞和分子自闭症谱系障碍（ASD）大脑过度生长的机制。