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 人脑发育过程中的电路形成包括以下几个步骤：(I)细胞命运指定，(Ii)增殖 和调节前体池的大小，以及(3)神经细胞迁移到其适当的位置以整合 进入本地赛道。年轻的中间神经元(IN)和少突胶质细胞前体(OPC)仍然是未成熟的 在发育过程中长期致力于谱系细胞，经历广泛的迁移和 人类发育中脑中神经回路整合前的晚期分化和髓鞘形成。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的伤害。我们的 该计划前一周期的发现突出了OPC和IN与血液的新的基质相互作用 正在开发中的船只。我们发现OPC使用血管系统作为迁移的物理支架 发展中枢神经系统(Tsai Science 2016 PMC5472053)，OPC驱动小鼠脑内白质血管生成 (袁Cell 2014 PMC4149873)，以及与血管系统相关的迁移的中间神经元簇。 人脑(Paredes Science 2016 PMC5436574)。然而，人们对细胞和 人OPC诱导血管生成和血管周围迁移的分子机制 人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血统指导？以及随后血管支架的建立是如何 亚型迁移中的中介和调控？这个项目试图了解这些现象背后的机制 人类新生儿脑内的突起。我们将1)评估参与OPC与内皮TIP相互作用的因素 细胞以及形态上的相互作用，确定候选的血管生成途径和新的TIP细胞标记 并探讨OPC-TIP细胞相互作用功能障碍在新生儿缺氧损伤中的作用。我们 将2)确定OPC编码的Wnt和VEGF配体在协调内皮细胞末端细胞中的功能作用 血管生成和对缺氧损伤的抵抗力，我们将3)鉴定血管的转录信号- 在人类新生儿脑中的相关迁移，并确定相关血管多样性与 非血管相关的IN迁移是对其发育起源的反映。了解蜂窝网络 人脑中OPC介导的血管生成和血管相关迁移的机制不会 只阐明了基本的生物过程，但将提供洞察如何发生失调 早产和足月缺氧，并为治疗干预的规划提供了前景。