Regulation of Cellular Pathwaysin Human Brain Development

描述（由申请人提供）：人类大脑的复杂性被认为是独一无二的，然而许多神经元和胶质亚型的起源及其在新生儿中迁移和整合到功能回路中的情况仍然知之甚少。此外，这些过程可能在缺氧性神经损伤中中断，从而导致死亡、脑瘫和/或长期认知障碍。该计划的重点是人类中间神经元（IN）和少突胶质细胞前体（OPC）在妊娠晚期（24-40周）的发育，以及谱系的个体发生、迁移和分化是否受氧水平和缺氧诱导因子（HIF）途径的调节。该项目是研究人员共同兴趣的产物，富有成效的合作，以及他们在加州大学旧金山分校Eli和Edythe Broad再生医学和干细胞研究所最近建成的Ray和Dagmar Dolby大楼实验室的密切联系。研究人员研究了人类胎儿和新生儿的大脑，最近发现了(1)外室下区（OSVZ），(2)内侧迁移流（MMS）年轻神经元的连锁迁移，(3)损伤对缺氧缺血性脑病（HIE）婴儿少突胶质细胞发育的影响。我们提出了三个项目和核心，以促进对人类大脑发育和损伤的理解。项目1研究年轻的INs迁移到人类新生儿大脑的焦点区域，它们的分化和氧调节通路对发育的影响。项目2将定义24-40周妊娠期人类OSVZ的结构和OPC的产生，以及氧气水平对谱系个体发生的调节。项目3将为HIE新生儿in和OPC群体中HIF通路的激活以及HIF通路基因在产前和产后in和OPC发育过程中的细胞内在功能提供直接证据。行政核心(A)负责预算监督、协调和取得资源。所有项目将使用原始人类神经病理标本进行组织学分析，并由神经病理学核心(B)支持。所有项目将采用动物实验系统。基于令人信服的初步数据，我们提出了一个动物模型核心(C)来支持新生儿雪貂大脑的研究。

DESCRIPTION (provided by applicant): Human brain complexity is considered unique, yet the genesis of many neuronal and glial sub-types and their migration and integration into functional circuits in neonates remains poorly understood. Moreover, these processes are likely disrupted in hypoxic neurological injuries, which can result in death, cerebral palsy and/or long-term cognitive disabilities. The proposed program focuses on human interneuron (IN) and oligodendrocyte precursor (OPC) development during 3rd trimester (24-40 weeks) gestation, and whether lineage ontogeny, migration and differentiation is regulated by oxygen levels and the hypoxia-inducible factor (HIF) pathway. This program is an outgrowth of the investigators common interests, productive collaborations and the close association of their laboratories in the recently built Ray and Dagmar Dolby Building in the Eli and Edythe Broad Institute for Regeneration Medicine and Stem Cell Research at UCSF. The investigators have studied the human fetal and newborn brain and recently identified (1) the outer subventricular zone (OSVZ), (2) chain migration of young neurons of medial migratory stream (MMS) and (3) the impact of injury on oligodendrocyte development in infants with hypoxic-ischemic encephalopathy (HIE). We propose three projects and cores to promote an understanding of human brain development and injury. Project 1 investigates migration of young INs to focal regions of human newborn brain, their differentiation and the developmental impact of oxygen- regulated pathways. Project 2 will define structure and OPC production of the human OSVZ from 24-40 weeks gestation, and regulation of lineage ontogeny by oxygen levels. Project 3 will provide direct evidence for HIF pathway activation in IN and OPC populations in human neonates with HIE, and cell-intrinsic functions of HIF pathway genes during pre- and post-natal IN and OPC development. The administrative core (A) provides budgetary oversight, coordination and access to resources. All projects will use primary human neuropathological specimens for histological analysis supported by a neuropathology core (B). All projects will employ animal experimental systems. Based on compelling preliminary data, we propose an animal model core (C) to support studies in neonatal ferret brain.