Development and Expansion of the Human Cerebral Cortex

人类大脑皮层的发育和扩展

• 批准号: 10539676
• 负责人: ARNOLD KRIEGSTEIN
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539676
• 关键词: Address; Architecture; Behavioral; Bioinformatics; Biological Models; Brain; Brain Diseases; Cells; Cerebral cortex; Cerebrum; Complement; Development; Disease; Etiology; Evolution; Genomics; Glioblastoma; Goals; Health; Human; Human Development; Mus; Neurodevelopmental Disorder; Neuroglia; Neurons; Organoids; Outcome; Population Analysis; Radial; Rattus; Rodent; Role; Schizophrenia; Signal Pathway; Signal Transduction; Structure; Study Subject; Therapeutic; Tissue Sample; Tissues; autism spectrum disorder; cell type; human disease; human model; human stem cells; in vitro Model; lissencephaly; malformation; nerve stem cell; neurogenesis; novel; progenitor; real-time images; stem cells; subventricular zone; therapy development

A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using “cerebral organoids”. Understanding human-specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the intracellular signaling networks that regulate IP cell expansion, investigate the role of distinct neurogenic niches in creating neuronal diversity, and examine neuron to progenitor signaling pathways that may regulate IPC neurogenesis. Additionally, we will explore the role of oRGs and IPCs in lissencephaly and related neurodevelopmental diseases, and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, real time imaging of primary tissue samples, and in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.

该提案的一个主要长期目标是了解人脑发育和神经发育疾病的起源。大脑皮层是一种结构，其中模型系统（例如小鼠或大鼠）可能无法捕获建筑的复杂性和与理解人类发展和疾病相关的功能。该提案旨在通过使用“大脑器官”来理解人类干细胞衍生的体外模型系统完成的原代组织的理解差距。了解人类发育的人类特定方面不仅对于理解神经发育障碍的病因至关重要，包括自闭症和精神分裂症以及最终开发疗法，而且还将有利于我们对人类皮质进化的理解，神经类型的多样性和血统，以及使我们独一无二的机制可帮助我们独特。发展中的人脑包含一个扩大的增殖区域，即啮齿动物中不存在的外室外区（OSVZ）。这项研究将针对OSVZ，外部辐射胶质（ORG）和中间祖细胞（IP）细胞中发现的两种最近发现的神经祖细胞类型。这些细胞类型特别重要，因为它们是人脑的巨大发展和进化扩展的基础。该提议旨在从其构造性组织的基因组，细胞和行为特征以及通过神经发生的关键阶段来阐明人类皮质发育的复杂性。我们计划发现谱系轨迹，这些谱系轨迹定义了祖细胞 - 实物关系并确定克隆后代的细胞命运。我们将使用新型的组织和IPC标记来富集祖细胞群进行分析，探索调节IP细胞扩展的细胞内信号传导网络，研究独特的神经源性壁细分市场在产生神经元多样性中的作用，并检查可调节IPC神经发生的神经元祖细胞信号通路。此外，我们将探讨组织和IPC在Lissuencephaly和相关神经发育疾病中的作用，并追求组织细胞与侵入性胶质母细胞瘤之间的有趣关系。这些雄心勃勃的目标是由于最近的技术进步而实现的，包括改善单细胞基因组学，生物信息学，原代组织样品的实时成像以及人类皮质发育的体外模型。结果有望改变我们对健康和疾病中人类脑发育的理解。