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.

理解人类脑的主要目标和神经发育局的起源旨在使我们对人类皮质发展的理解差距的差距是由人类干细胞衍生的体外模型系统汇编的主要SUE的研究，了解脑毒素发展的人类特异性方面不仅对神经发育的病因至关重要，包括自闭症和自闭症和精神分裂症最终会开发疗法，但也将使我们对人类皮质进化的理解和皮质膨胀的机制有助于定义使发展中的人类包含啮齿动物的扩散区域。最近发现的神经祖细胞类型基础是OSVZ，外部辐射胶质（ORG）和国际祖细胞（IP）细胞，这些细胞类型尤为重要。从基因组，细胞和行为特征的角度来阐明人类皮质发育的复杂性。克隆下降的命运探索在lissentencephaly和相关的神经发育疾病中的作用和IPC，这是由于最近的技术进步，生物信息学，现实时代的现实时代图像，因此，这些雄心勃勃的目标是可见的有望改变健康和疾病中的人脑速度。