Project 2: Mechanisms underlying oligodendrocyte precursor-mediated angiogenesis and interneuron vessel-associated migration in human neonatal brain

项目2：人类新生儿脑中少突胶质细胞前体介导的血管生成和中间神经元血管相关迁移的机制

• 批准号: 10408734
• 负责人: Stephen Philip James Fancy
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408734
• 关键词: Animals; Arteries; Biological Process; Blood Vessels; Brain; Brain Hypoxia; Candidate Disease Gene; Cell Communication; Cell Lineage; Cell Nucleus; Cells; Cerebral Palsy; Cerebrovascular system; Chronic; Data; Development; Embryo; Endothelium; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Human; Hypoxia; In Situ; Infant; Injury; Intellectual functioning disability; Interneurons; Ligands; Light; Maps; Mediating; Molecular; Morphology; Motor Neurons; Mus; Nature; Neonatal; Nervous System Trauma; Neurons; Oligodendroglia; Pathway interactions; Positioning Attribute; Premature Birth; Process; Regulation; Reporting; Rodent; Role; Science; Specific qualifier value; Spinal; Telencephalon; Testing; Therapeutic Intervention; Time; Up-Regulation; Vascular Endothelial Growth Factors; Vascularization; angiogenesis; arteriole; cell fate specification; cell growth regulation; cell type; hypoxia neonatorum; insight; migration; myelination; neonatal brain; neonatal human; neonatal hypoxic-ischemic brain injury; neonatal injury; neonate; neural circuit; neurogenetics; novel; novel marker; oligodendrocyte lineage; oligodendrocyte precursor; programs; resilience; scaffold; therapeutic development; transcriptome sequencing; transcriptomics; white matter

Project 2 Abstract Circuit formation in developing human brain involves sequential steps of: (i) cell fate specification, (ii) proliferation and regulation of precursor pool size, and (iii) migration of neural cells to their appropriate position to integrate into local circuits. Young interneurons (IN) and oligodendrocyte precursors (OPCs) persist as immature yet committed lineage cells for a protracted period of time during development, undergoing extensive migration and late differentiation before integration into/and myelination of neural circuits in human developing brain. This relatively long developmental time course means that they may be more vulnerable to neonatal injury. Our findings in the prior cycle of this program highlighted novel stromal interactions of OPCs and IN with blood vessels during development. We identified that OPCs use vasculature as a physical scaffold for migration in the developing CNS (Tsai Science 2016 PMC5472053), that OPCs drive white matter angiogenesis in mouse brain (Yuen Cell 2014 PMC4149873), and that migrating clusters of interneurons associate with the vasculature in the human brain (Paredes Science 2016 PMC5436574). However, very little is understood about the cellular and molecular mechanisms that underlie human OPC induced angiogenesis and IN perivascular migration, a phenomenon unique to human brain development. What are the cellular mechanisms that underlie angiogenesis directed by OL lineage in human brain? And how does the establishment of a vascular scaffold subsequently mediate and regulate IN sub-type migration? This project seeks to understand mechanisms underlying these processes in human neonatal brain. We will 1) evaluate factors involved in OPC interaction with endothelial tip cells as well as the morphological interaction, identify candidate angiogenic pathways and novel tip cell markers in human brain, and investigate dysfunction of OPC-tip cell interactions in human neonatal hypoxic injury. We will 2) determine a functional role for OPC-encoded Wnt and VEGF ligands in orchestrating endothelial tip cell angiogenesis and in resilience to hypoxic injury, and we will 3) identify the transcriptomic signature of vessel- associated migrating IN in human neonatal brain, and determine whether diversity of vessel associated versus non-vessel associated IN migration is a reflection on their developmental origin. Understanding the cellular mechanisms mediating OPC-mediated angiogenesis and IN vessel-associated migration in human brain will not only elucidate fundamental biological processes, but will provide insight into how dysregulation could occur in preterm birth and term hypoxia and provide perspective for the planning for therapeutic interventions.

项目2 发育中的人脑回路形成涉及以下顺序步骤：（i）细胞命运特化，（ii）增殖 和调节前体池的大小，以及（iii）神经细胞迁移到其适当的位置以整合 进入本地电路。年轻的中间神经元（IN）和少突胶质细胞前体（OPCs）仍然不成熟， 定型谱系细胞在发育过程中持续很长一段时间，经历广泛的迁移， 在人类发育中的大脑中，在整合到神经回路中之前的晚期分化和髓鞘形成。这 相对较长的发育时间过程意味着他们可能更容易受到新生儿损伤。我们 在该项目的前一个周期中的发现强调了OPCs和IN与血液的新型基质相互作用 船在发展中。我们发现，OPCs使用血管作为迁移的物理支架， 开发CNS（Tsai Science 2016 PMC 5472053），OPC驱动小鼠脑中的白色物质血管生成 (Yuen Cell 2014 PMC 4149873），并且中间神经元的迁移簇与神经元中的脉管系统相关。 人脑（Paredes Science 2016 PMC 5436574）。然而，很少有人了解细胞和 人OPC诱导血管生成和IN血管周围迁移的分子机制， 人类大脑发育所特有的现象。血管生成的细胞机制是什么 由人类大脑中的OL谱系指导？接下来血管支架的建立 介导和调节IN亚型迁移？该项目旨在了解这些机制的基础上， 人类新生儿大脑的过程。我们将1）评估OPC与内皮尖端相互作用的相关因素 细胞以及形态学的相互作用，确定候选血管生成途径和新的尖端细胞标志物 在人脑中，并研究在人类新生儿缺氧损伤中OPC-尖端细胞相互作用的功能障碍。我们 将2）确定OPC编码的Wnt和VEGF配体在协调内皮尖端细胞中的功能作用， 血管生成和对缺氧损伤的恢复，我们将3）确定血管的转录组学特征， 相关的迁移性IN在人类新生儿脑，并确定是否血管相关的多样性与 非血管相关的IN迁移是其发育起源的反映。了解细胞 在人脑中，介导OPC介导的血管生成和IN血管相关迁移的机制将不会 它只阐明了基本的生物学过程，但将提供洞察如何失调可能发生在 早产和足月缺氧，并提供治疗干预计划的前景。