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: 10627968
• 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/10627968
• 关键词: Animals; Arteries; Biological Process; Blood Vessels; Brain; Brain Ischemia; Candidate Disease Gene; Cell Communication; Cell Lineage; 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; Maps; Mediating; Molecular; Morphology; Motor Neurons; Mus; Nature; Neonatal; Nervous System Trauma; Neurons; Oligodendroglia; Pathway interactions; Positioning Attribute; Premature Birth; Process; Proliferating; Regulation; Reporting; Rodent; Role; Science; Specific qualifier value; Spinal; Telencephalon; Testing; Therapeutic Intervention; Time; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; Vascularization; Vertebral column; angiogenesis; arteriole; candidate identification; candidate validation; cell fate specification; cell growth regulation; cell type; gene conservation; 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; single nucleus RNA-sequencing; therapeutic development; 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 人类大脑发育中的回路形成涉及以下连续步骤：(i) 细胞命运规范，(ii) 增殖 和前体库大小的调节，以及（iii）神经细胞迁移到适当的位置进行整合 进入本地电路。年轻的中间神经元 (IN) 和少突胶质细胞前体 (OPC) 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，经历广泛的迁移和 人类发育大脑中神经回路整合/和髓鞘化之前的晚期分化。这 相对较长的发育时间意味着他们可能更容易受到新生儿伤害。我们的 该计划前一个周期的研究结果强调了 OPC 和 IN 与血液的新型基质相互作用 开发期间的船只。我们发现 OPC 使用脉管系统作为迁移的物理支架。 发育中枢神经系统（Tsai Science 2016 PMC5472053），OPCs 驱动小鼠大脑白质血管生成 （Yuen Cell 2014 PMC4149873），并且迁移的中间神经元簇与血管系统相关 人脑（Paredes Science 2016 PMC5436574）。然而，人们对细胞和 人类 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 由人脑中的OL谱系指导？随后血管支架的建立又是如何进行的呢？ 介导和调节IN亚型迁移？该项目旨在了解这些背后的机制 人类新生儿大脑中的过程。我们将 1) 评估 OPC 与内皮尖端相互作用所涉及的因素 细胞以及形态学相互作用，识别候选血管生成途径和新的尖端细胞标记 人脑中，并研究人类新生儿缺氧损伤中 OPC-tip 细胞相互作用的功能障碍。我们 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能力，我们将3）鉴定血管的转录组学特征- 人类新生儿大脑中相关的迁移性IN，并确定血管多样性是否与相关 非血管相关的 IN 迁移反映了它们的发育起源。了解细胞 人脑中介导 OPC 介导的血管生成和 IN 血管相关迁移的机制不会 仅阐明基本的生物过程，但将提供有关失调如何发生的见解 早产和足月缺氧，并为治疗干预的规划提供视角。