Development and Expansion of the Human Cerebral Cortex

人类大脑皮层的发育和扩展

• 批准号: 9481453
• 负责人: ARNOLD KRIEGSTEIN
• 金额: $ 4.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9481453
• 关键词: Address; Architecture; Autistic Disorder; Behavioral; Bioinformatics; Biological Models; Brain; Brain Diseases; Cells; Cerebral cortex; Cerebrum; Complement; Development; Disease; Etiology; Evolution; Genomics; Glioblastoma; Goals; Health; Human; Human Development; Image; Mus; Neurodevelopmental Disorder; Neuroglia; Neurons; Organoids; Outcome; Population Analysis; Radial; Rattus; Rodent; Role; Schizophrenia; Signal Pathway; Signal Transduction; Stem cells; Structure; Study Subject; Therapeutic; Time; Tissue Sample; Tissues; cell type; human disease; human stem cells; in vitro Model; lissencephaly; malformation; nerve stem cell; neurogenesis; novel; progenitor; 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.

这项提议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。大脑皮层是一种结构，在这里，模型系统，如小鼠或大鼠，可能无法捕捉到与理解人类发育和疾病相关的结构和功能的复杂性。这项建议旨在解决我们对人类皮质发育的理解上的差距，方法是通过研究原始组织，辅以人类干细胞衍生的体外模型系统，使用“脑器官”。了解人类大脑发育的特定方面不仅对于了解包括自闭症和精神分裂症在内的神经发育障碍的病因以及最终开发治疗方法至关重要，而且还将有助于我们理解人类皮质的进化、神经细胞类型的多样性和谱系以及皮质扩张的机制-它将有助于定义是什么使我们独一无二。发育中的人脑包含一个扩大的增殖区，即啮齿类动物没有的外脑室下区(OSVZ)。这项研究将针对最近在OSVZ中发现的两种神经前体细胞类型，外径向神经胶质细胞(Org)和中间前体细胞(IP)。这些细胞类型尤其重要，因为它们构成了人脑巨大的发育和进化扩张的基础。这一建议试图从其组成组织和IP神经前体细胞及其后代在神经发生的关键阶段的基因组、细胞和行为特征方面阐明人类皮质发育的复杂性。我们计划发现定义祖先-后代关系的谱系轨迹，并决定克隆后代的细胞命运。我们将使用新的org和IPC标记来丰富祖细胞群体进行分析，探索调控IP细胞扩张的细胞内信号网络，研究不同的神经源性生态位在创造神经元多样性中的作用，并研究可能调控IPC神经发生的神经元到祖细胞的信号通路。此外，我们还将探索Orgs和IPC在无脑和相关神经发育疾病中的作用，并探索org细胞和侵袭性胶质母细胞瘤之间有趣的关系。由于最近的技术进步，这些雄心勃勃的目标是可以实现的，包括单细胞基因组学、生物信息学、初级组织样本的实时成像以及人类皮质发育的体外模型。这一结果有望改变我们对人类大脑发育在健康和疾病方面的理解。