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摘要 发育中的人脑中的电路形成涉及以下顺序步骤：（i）细胞命运规范，（ii）增殖 和调节前体池大小，以及（iii）神经细胞迁移到其合适的位置以整合的位置 进入当地电路。年轻的中间神经元（IN）和少突胶质细胞前体（OPC）仍然不成熟 在发育期间，持久的谱系细胞在旷日持久的时间段内，经历了广泛的迁移和 在整合到人类发育中的大脑中的神经回路之前的较晚分化。这 相对较长的发育时间课程意味着它们可能更容易受到新生儿损伤的影响。我们的 该程序的先前周期中的发现突出了OPC的新型基质相互作用和血液 发育过程中的船只。我们确定OPC使用脉管系统作为物理支架，用于迁移 开发CNS（TSAI Science 2016 PMC5472053），OPC驱动小鼠脑中的白质血管生成 （Yuen Cell 2014 PMC4149873），以及与脉管系统相关的中间神经元簇 人脑（Paredes Science 2016 PMC5436574）。但是，关于细胞和 人类OPC诱导血管生成和血管周围迁移的分子机制 人脑发育独有的现象。基于血管生成的细胞机制是什么 由OL Lineage在人脑中指导？然后如何建立血管支架 在亚型迁移中进行中介和调节？该项目旨在了解这些项目的基础 人类新生儿大脑的过程。我们将1）评估与内皮尖端相互作用涉及的因素 细胞以及形态相互作用，鉴定候选血管生成途径和新型尖端细胞标记 在人脑中，研究人类新生儿低氧损伤中OPC细胞相互作用的功能障碍。我们 将2）确定OPC编码的Wnt和VEGF配体在策划内皮尖端细胞中的功能作用 血管生成和对低氧损伤的韧性，我们将确定血管的转录组特征 与人类新生儿大脑迁移的相关性，并确定血管的多样性是否相关 与迁移相关的非血管反映了它们的发育起源。了解细胞 介导OPC介导的血管生成和血管相关迁移的机制不会 仅阐明基本生物学过程，但会提供有关如何发生失调的洞察力 早产和期限缺氧，并为治疗干预措施计划提供了观点。