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类大脑发育和神经发育疾病的起源。大脑皮层是一种模型系统（例如小鼠或大鼠）可能无法捕获与理解人类发育和疾病相关的结构和功能的复杂性的结构。该提案旨在通过使用“大脑类器官”对原代组织进行研究，并辅之以人类干细胞衍生的体外模型系统，从而弥补我们对人类皮质发育理解上的差距。了解人类大脑发育的特定方面不仅对于了解神经发育障碍（包括自闭症和精神分裂症）的病因以及最终开发治疗方法至关重要，而且还将有利于我们了解人类皮质进化、神经细胞类型的多样性和谱系以及皮质扩张机制 - 它将有助于定义我们的独特之处。发育中的人类大脑包含扩大的增殖区域，即外部脑室下区（OSVZ），而啮齿动物中不存在这种区域。这项研究将针对 OSVZ 中最近发现的两种神经祖细胞类型：外放射状胶质细胞 (oRG) 和中间祖细胞 (IP)。这些细胞类型特别重要，因为它们是人类大脑巨大发育和进化扩张的基础。该提案旨在阐明人类皮质发育的复杂性，包括其组成部分 oRG 和 IP 神经祖细胞及其后代在神经发生关键阶段的基因组、细胞和行为特征。我们计划发现定义祖代关系并确定克隆后代细胞命运的谱系轨迹。我们将使用新型 oRG 和 IPC 标记来富集祖细胞群进行分析，探索调节 IP 细胞扩增的细胞内信号网络，研究不同的神经源性生态位在创建神经元多样性中的作用，并检查可能调节 IPC 神经发生的神经元到祖细胞的信号通路。此外，我们将探讨 oRG 和 IPC 在无脑畸形和相关神经发育疾病中的作用，并探究 oRG 细胞和侵袭性胶质母细胞瘤之间的有趣关系。这些雄心勃勃的目标之所以能够实现，得益于最新的技术进步，包括单细胞基因组学、生物信息学、原代组织样本的实时成像以及人类皮质发育的体外模型的改进。这一结果有望改变我们对健康和疾病中人类大脑发育的理解。