The Development of Germinal Zones in the Human Brain

人脑生发区的发育

• 批准号: 7328131
• 负责人: Nader Sanai
• 金额: $ 5.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-02 至 2008-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328131
• 关键词: Address; Adult; Age; Brain; Brain Neoplasms; Brain Stem; Brain Stem Glioma; Cell Culture Techniques; Cell Line; Cells; Cerebellum; Cerebral cortex; Childhood; Childhood Brain Neoplasm; Class; DNA Microarray Chip; DNA Microarray format; Data; Development; Electron Microscopy; Gene Expression; Genes; Histology; Human; Immunohistochemistry; In Situ; Intracranial Neoplasms; Lateral; Life; Literature; Localized; Microarray Analysis; Molecular; Molecular Profiling; Neurons; Pathway interactions; Pattern; Play; Population; Primates; Prosencephalon; Regulation; Rodent; Role; Staging; Stem cells; Stream; Structure; Techniques; Time; Tissues; Work; base; combinatorial; developmental neurobiology; fetal; functional genomics; human disease; in vivo; interest; lateral ventricle; migratory population; nerve stem cell; neuro-oncology; neuroblast; novel; olfactory bulb; outcome forecast; progenitor; programs; reconstruction; relating to nervous system; stem; stem cell fate; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): We now know that neural stem cells persist in restricted regions of the adult human brain. The subventricular zone (SVZ) is the largest such region, yet in humans its function remains unknown. In contrast to every other studied vertebrate, including primates, the human SVZ does not appear to generate neurons for the olfactory bulb, but contains a robust ribbon of multipotent, self-renewing astrocytic neural stem cells that lines the lateral ventricles. Unfortunately, nearly every study of the human SVZ is based upon adult tissue. The proposed work will characterize the cellular composition and transcriptional expression patterns of fetal and pediatric human germinal zones. Using a combination of tissue histology, electron microscopy, and cell culture techniques, we will define the cytoarchitecture of these regions and identify their progenitor populations. Concurrently, through a functional genomics approach, we will determine the spatial and stage-specific expression of essential transcription factors selected through DNA microarray analysis. Our hypothesis is that progenitor cells of the developing human SVZ can be identified by combinatorial expression of transcription factors. A corollary of this hypothesis is that such transcription factors may also regulate the fate and potential of such cells in vivo. This combined phenotypic and genotypic study of fetal and pediatric human germinal zones will not only identify novel human neural stem cell populations and migratory streams, but will also highlight the molecular pathways conserved across human neural stem development and pediatric brain tumor formation. The emerging connection between developmental neurobiology and neuro-oncology suggests that pediatric human brain tumors such as brainstem gliomas may be driven by underlying progenitor cell populations. Pediatric brainstem gliomas represent 10-25% of all pediatric intracranial tumors and typically carry a very poor prognosis. Defining the structure and function of developing human germinal regions may clarify the role neural stem cells play in pediatric tumorigenesis.

描述（由申请人提供）：我们现在知道，成人人脑的受限区域中神经干细胞持续存在。脑室下区（SVZ）是最大的此类区域，但在人类中，其功能尚不清楚。与包括灵长类动物在内的其他所有研究的脊椎动物相反，人类SVZ似乎并未为嗅球产生神经元，而是包含一条强大的多型，自我更新的星形胶质细胞神经干细胞，使侧心室的线条。不幸的是，对人类SVZ的几乎每项研究都基于成人组织。所提出的工作将表征胎儿和小儿人发育区的细胞组成和转录表达模式。使用组织组织学，电子显微镜和细胞培养技术的组合，我们将定义这些区域的细胞结构并确定其祖细胞种群。同时，通过功能基因组学方法，我们将确定通过DNA微阵列分析选择的基本转录因子的空间和特定阶段表达。我们的假设是，可以通过转录因子的结合表达来鉴定发展的人类SVZ的祖细胞。这种假设的必然性是，这种转录因子还可以调节体内此类细胞的命运和潜力。这种对胎儿和小儿人生发区域的表型和基因型研究的结合不仅将鉴定出新型的人类神经干细胞群体和迁移流，而且还将突出显示在人类神经茎发育和小儿脑肿瘤形成中保守的分子途径。发育神经生物学和神经肿瘤学之间的新兴联系表明，儿科人脑肿瘤（如脑干神经胶质瘤）可能是由潜在的祖细胞群体驱动的。小儿脑干神经胶质瘤占所有小儿颅内肿瘤的10-25％，通常具有非常差的预后。定义发展人类生发区域的结构和功能可以阐明神经干细胞在小儿肿瘤发生中的作用。