Regulation of Cellular Pathwaysin Human Brain Development

描述(申请人提供)：人类大脑的复杂性被认为是独一无二的，然而许多神经元和神经胶质亚型的起源以及它们在新生儿中的迁移和整合到功能回路仍然知之甚少。此外，这些过程可能在缺氧性神经损伤中中断，这可能导致死亡、脑瘫和/或长期认知障碍。该计划的重点是妊娠晚期(24-40周)人中间神经元(IN)和少突胶质前体细胞(OPC)的发育，以及血统个体发育、迁移和分化是否受氧气水平和低氧诱导因子(HIF)途径的调节。该项目是研究人员共同兴趣、富有成效的合作以及他们的实验室在加州大学旧金山分校ELI和Edythe布罗德再生医学和干细胞研究中心最近建造的Ray和Dagmar Dolby大楼密切合作的结果。研究人员对胎儿和新生儿的脑进行了研究，最近发现了(1)外室下区(OSVZ)，(2)内侧迁移流(MMS)年轻神经元的链迁移，(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，以促进对人脑发育和损伤的了解。项目1调查年轻的INS迁移到人类新生儿大脑的焦点区域，它们的分化以及氧调节通路对发育的影响。项目2将定义怀孕24-40周的人类OSVZ的结构和OPC的产生，以及氧气水平对谱系个体发育的调节。项目3将为HIE新生儿IN和OPC群体中HIF途径的激活以及HIF途径基因在出生前和出生后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)提供预算监督、协调和获得资源。所有项目将使用原始人类神经病理标本进行组织分析，并由神经病理学核心(B)提供支持。所有项目都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CORE(C)来支持对新生雪貂大脑的研究。

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.