Regulation of Cellular Pathwaysin Human Brain Development

人脑发育中细胞通路的调节

基本信息

批准号：
8881350
负责人：
DAVID H ROWITCH
金额：
$ 134.54万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881350
关键词：
Alleles Animal Model Animals Area Axon Behavior Brain Brain Injuries Brain region Cell Proliferation Cell division Cells Cerebral Palsy Cessation of life Chain Migrations Characteristics Collaborations Conflict (Psychology)Data Development Dorsal Evaluation Ferrets Fiber Genes Genetic study Gestational Age Goals Growth Health Housing Human Hypoxia Hypoxia-Inducible Factor Pathway Hypoxic Brain Damage Immigration Infant Injury Institutes Interneurons Laboratories Location Magnetic Resonance Imaging Maps Medial Medicine Modeling Natural regeneration Neocortex Neonatal Nervous System Trauma Neurons Neurosciences Newborn Infant Oligodendroglia Online Systems Operative Surgical Procedures Oxygen Oxygen measurement, partial pressure, arterial Pathway interactions Population Pregnancy Process Production Publishing Radial Regulation Research Research Personnel Resources Rodent Role Sampling Specimen Staging Stem Cell Research Stream Structure System Techniques Testing Time Work adjudicate base cell growth regulation cell type cognitive disability data sharing fetal hypoxia inducible factor 1 insight interest loss of function member migration neonatal hypoxic-ischemic brain injury neonate neurogenesis neuropathology novel oligodendrocyte lineage oligodendrocyte precursor postnatal precursor cell progenitor programs public health relevance scaffold subventricular zone

项目摘要

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.

描述（由申请人提供）：人脑复杂性被认为是独特的，但是许多神经元和神经胶质亚型的起源及其迁移和整合在新生儿的功能回路中仍然知之甚少。此外，这些过程可能会因缺氧神经损伤而破坏，这可能导致死亡，脑瘫和/或长期认知障碍。提出的计划侧重于在第三个三个月（24-40周）妊娠期间人类中间神经元（IN）和少突胶质细胞前体（OPC）发育，以及谱系个体发育，迁移和分化是否受氧气和低氧诱导因子（HIF）途径的调节。该计划是调查人员的共同利益，生产性合作以及其实验室在最近建造的Ray和Dagmar Dolby建筑中的实验室的密切关联，以及UCSF的Edythe Receneration Medicine and Stem Bell研究所。研究人员已经研究了人类胎儿和新生大脑，最近鉴定出（1）外室下区（OSVZ），（2）（2）内侧迁移流（MMS）的年轻神经元的链迁移以及（3）损伤对少突胶质细胞发育的影响低氧性脑炎（低氧性脑病）。我们提出了三个项目和核心，以促进对人脑发育和伤害的理解。项目1调查了年轻的INS向人类新生儿大脑的焦点区域的迁移，其分化和氧气调节途径的发育影响。项目2将从24-40周的妊娠中定义人类OSVZ的结构和OPC产生，并根据氧气水平调节谱系本体发育。项目3将为HIE的人类新生儿中的HIF途径激活HIF途径的直接证据，以及HIF途径基因的细胞内部基因和OPC发育后HIF途径基因的细胞内部功能。行政核心（a）提供了预算监督，协调和对资源的访问。所有项目都将使用原发性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。所有项目都将采用动物实验系统。基于引人注目的初步数据，我们建议动物模型核心（C）支持新生儿雪貂脑的研究。