PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS

嗅觉神经发生中的基因表达程序

• 批准号: 7900794
• 负责人: JOHN J. NGAI
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900794
• 关键词: Adult; Afferent Neurons; Axon; Biological; Cells; Complex; DNA Microarray Chip; Data Set; Development; Embryonic Development; Environment; Gene Expression; Generations; Genes; Genetic; Genetic Programming; Human Genome; In Situ Hybridization; Individual; Lead; Lesion; Life; Microarray Analysis; Molecular Profiling; Monitor; Multipotent Stem Cells; Mus; Mutant Strains Mice; Natural regeneration; Nervous system structure; Neuraxis; Neurons; Neurophysiology - biologic function; Olfactory Epithelium; Pathway interactions; Pattern; Process; Property; RNA; Series; Staging; Stem cells; Synapses; System; Techniques; Time; Transcript; Validation; base; cell motility; cell type; complex biological systems; genome-wide; insight; molecular marker; mutant; nerve stem cell; neurogenesis; progenitor; programs; relating to nervous system; research study

The generation of neuronal diversity in the nervous system is a complex process involving the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the determination and proliferation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. Most of these steps are controlled by specific gene expression programs, such as cell fate decisions that lead to the generation of neuronal precursors. The genetic programs underlying the differentiation of mature neurons from their progenitors remain largely unknown, however, in part because of the difficulty in studying neuronal stem cells in their native environments. In the vertebrate olfactory system, primary sensory neurons are continuously regenerated throughout adult life via the proliferation and differentiation of neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on the properties of neuronal stem cells. While some stages of this lineage have been identified with a limited set of molecular markers, the genetic programs that both define and regulate olfactory neurogenesis remain largely unknown. The enormous complexity inherent in this biolo,qical _roblem demands a .qlobal view of .qene expression in order to fully understand the ,qenetic networks Jnderlyin.q neural function and development in this developmental system. In this application we propose a suite of DNA microarray-based techniques to identify - on a ,qlobal scale - patterns of .qene expression correspondin.q to distinct sta.qes of the olfactory neuron linea,qe. We propose (1) to perform temporal profiling of gene expression in olfactory epithelium during embryonic development and lesion-induced regeneration to identify the genes and gene expression programs associated with distinct stages of this lineage, including the earliest multipotent progenitor stage; and (2) to refine this analysis by comparing gene expression patterns in mutants known to disrupt olfactory neurogenesis, and to validate the microarray-based predictions by RNA in situ hybridizations. Our approach is expected to yield highly detailed information about the molecules and pathways responsible for the genesis of olfactory sensory neurons from their progenitor cells. In addition, a broader panel of molecular markers will be generated for distinct stages of olfactory neurogenesis. The elucidation of these ,qenetic pro,qrams at the ,qenome-wide level will provide valuable insi.qhts into the properties of pro,qenitor stem cells from a variety of neural and non-neural systems.

神经系统中神经元多样性的产生是一个复杂的过程，涉及规范 以及多种细胞谱系的分化。连续的发展计划控制着 个体神经元类型的确定和增殖、细胞迁移、轴突延伸以及最终的 功能性突触连接的形成。这些步骤大部分是由特定的基因表达控制的 程序，例如导致神经元前体生成的细胞命运决定。遗传性 成熟神经元与其祖细胞分化的潜在程序仍然很大程度上未知， 然而，部分原因是在天然环境中研究神经元干细胞很困难。 在脊椎动物嗅觉系统中，初级感觉神经元在整个成年过程中不断再生 通过神经祖细胞的增殖和分化来维持生命。这一功能使得嗅觉系统 特别适用于神经元干细胞特性的研究。虽然这个谱系的某些阶段 已通过一组有限的分子标记进行了鉴定，这些分子标记既定义又定义了遗传程序 调节嗅觉神经发生仍然很大程度上未知。这种生物学固有的巨大复杂性 _roblem 需要 .qene 表达式的 .qlobal 视图，以便充分理解 ,qenetic 网络 Jnderlyin.q 该发育系统中的神经功能和发育。 在此应用中，我们提出了一套基于 DNA 微阵列的技术来识别（在全球范围内） qene 表达模式对应于嗅觉神经元线的不同 sta.qes，qe。我们建议（1） 对胚胎发育过程中嗅觉上皮的基因表达进行时间分析 损伤诱导再生，以鉴定与不同的相关基因和基因表达程序 该谱系的各个阶段，包括最早的多能祖阶段； (2) 通过以下方式完善此分析 比较已知破坏嗅觉神经发生的突变体的基因表达模式，并验证 通过 RNA 原位杂交进行基于微阵列的预测。 我们的方法有望产生有关分子和途径的非常详细的信息 嗅觉感觉神经元从其祖细胞中起源。此外，更广泛的面板 将为嗅觉神经发生的不同阶段生成分子标记。这些的阐明 ,qenetic pro,qrams 在 ,qenome 范围内将为 pro,qenitor 的属性提供有价值的 insi.qhts 来自各种神经和非神经系统的干细胞。