Human cerebral organoids as a model system for neural development and disease

人类大脑类器官作为神经发育和疾病的模型系统

• 批准号: 10478865
• 负责人: Momoko Watanabe
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478865
• 关键词: 3-Dimensional; Affect; Animal Model; Apical; Architecture; Attention; BMP4; Biological Models; Brain; Cell Maintenance; Cells; Cerebral cortex; Cerebrum; Characteristics; Creativeness; Defect; Development; Disease; Disease model; Electrophysiology (science); Embryonic Development; Ethics; Exhibits; FMR1; Failure; Fragile X Syndrome; Gene Expression; Generations; Genetic; Goals; Heritability; Human; Human Development; Impaired cognition; Individual; Infection; Inherited; Lead; Ligands; Link; Long-Term Depression; Long-Term Potentiation; Medical Research; Methods; Modeling; Molecular; Morphogenesis; Mus; Mutation; Neocortex; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Organ; Organism; Organoids; Patients; Phenotype; Primates; Process; Production; Property; Proteins; Protocols documentation; Publishing; Radial; Reproducibility; Rodent; Rodent Model; Role; Schizophrenia; Sensory; Signal Transduction; Sister; Structure; Symptoms; Synapses; Synaptic plasticity; System; Techniques; Technology; Testing; Thinking; Tissues; Transforming Growth Factor beta; Transgenic Animals; autism spectrum disorder; brain tissue; differentiation protocol; human disease; human pluripotent stem cell; human tissue; in vitro Model; in vivo; induced pluripotent stem cell; insight; interest; neocortical; nerve stem cell; nervous system disorder; neural circuit; neural network; neurodevelopment; neurogenesis; neuropsychiatric disorder; novel; predict clinical outcome; progenitor; relating to nervous system; small molecule inhibitor; success; transcriptome; transcriptome sequencing; transcriptomics; zygote

Project Summary/Abstract It is intriguing how a single fertilized egg divides and gives rise to an organism containing a diverse array of cells, tissues, and organs with beautiful three-dimensional (3D) architecture in a precise manner. The neocortex is of particular interest because it is highly-specialized structure with features that are markedly different between species. For example, the neocortex in primates is enormously increased in size and complexity, which probably endow humans with remarkable sensory activities and intellectual ability such as abstract thinking and creativity. Understanding human corticogenesis is important for not only to gain some evolutionary insights but also to discover the underlying causes of human-specific diseases such as neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. We ideally need a human brain model, given that rodent models sometimes fail to mimic human symptoms and predict clinical outcomes. However, due to limited access to human brain tissue and ethical concerns, it has been challenging to directly study human development. Consequently, considerable attention has been placed on the generation of in vitro models using human pluripotent stem cells (hPSCs) to recapitulate aspects of human development and disease. The cerebral organoid is a 3D cortical tissue derived from hPSCs and recapitulates laminar organization of the developing cerebral neocortex in vivo. The advent of such organoid techniques has opened the door for studies of human specific developmental features and paves the way for disease modeling. However, many organoid differentiation protocols are inefficient and inconsistent and display marked variability in their ability to recapitulate the 3D architecture and course of neurogenesis in the developing human brain. The goal of this proposal is to understand 1) the state of hPSCs that can predict efficient and successful organoid differentiation, 2) to use this robust organoid system to uncover microcircuit formation that has the underlying importance for human brain activities and its malfunction is likely link to neuropsychiatric disorders, such as autism, and 3) to study Fragile X Syndrome, the most common heritable form of cognitive impairment, using human cortical organoids that can give some human-specific insights into mechanisms and cures of this disease.

项目总结/摘要 一个受精卵是如何分裂并产生一个含有多种多样的生物体的，这是很有趣的。 细胞，组织和器官以精确的方式具有美丽的三维（3D）结构。的 新皮层是特别感兴趣的，因为它是高度专业化的结构，具有明显的特征， 物种之间的差异。例如，灵长类动物的新皮层在大小上大大增加， 复杂性，这可能赋予人类非凡的感官活动和智力能力， 抽象思维和创造力。了解人类皮质发生不仅对获得一些 进化的见解，而且还发现人类特有疾病的根本原因， 神经发育障碍、神经变性障碍和神经精神障碍。我们需要一个人类的大脑 鉴于啮齿动物模型有时无法模拟人类症状并预测临床结果，因此， 然而，由于人类脑组织的有限获取和伦理问题，直接 研究人类发展。因此，相当多的注意力已经放在体外的产生上。 使用人类多能干细胞（hPSC）来概括人类发育的各个方面的模型， 疾病脑类器官是来源于hPSC的3D皮质组织， 组织发育中的大脑新皮层在体内。这种类器官技术的出现开启了 为研究人类特定的发育特征打开了大门，并为疾病建模铺平了道路。 然而，许多类器官分化方案是低效的和不一致的，并且显示出显著的可变性 在他们的能力，以概括的3D架构和过程中的神经发生在发育中的人类大脑。 该提案的目标是了解1）可以预测高效和成功的hPSC状态 类器官分化，2）使用这种强大的类器官系统来揭示微电路的形成， 人脑活动及其功能障碍的潜在重要性可能与神经精神疾病有关， 如自闭症，3）研究脆性X综合征，最常见的认知障碍遗传形式， 使用人类皮质类器官，可以提供一些人类特定的见解，了解这种机制和治疗方法， 疾病