Programs of Gene Expression in Olfactory Neurogenesis

嗅觉神经发生中的基因表达程序

• 批准号: 8460932
• 负责人: JOHN J. NGAI
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460932
• 关键词: Adult; Afferent Neurons; Animals; Apoptosis; Axon; Basal Cell; Cell Maintenance; Cell Proliferation; Cell division; Cell physiology; Cells; Complex; Degenerative Disorder; Development; Environment; Epidermis; Epithelial; Epithelium; Family; Family member; Foundations; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Programming; Genome; Individual; Injury; Investigation; Knock-out; Learning; Life; Mediating; Mitotic; Modeling; Molecular; Multipotent Stem Cells; Natural regeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Olfactory Epithelium; Play; Process; Proliferating; Property; Regulation; Replacement Therapy; Research; Reserve Stem Cell; Rest; Role; Sensory; Series; Site; Staging; Stem cells; Stratification; Stratified Epithelium; Structure; Study models; Synapses; System; Testing; Therapeutic; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; cell motility; cell type; chromatin immunoprecipitation; deep sequencing; genetic profiling; in vivo; insight; interest; loss of function; member; molecular marker; mutant; nerve stem cell; neuroepithelium; neurogenesis; new therapeutic target; postnatal; precursor cell; progenitor; programs; reconstitution; regenerative; relating to nervous system; response to injury; self renewing cell; self-renewal; therapy development; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): The generation of neuronal diversity in the nervous system requires the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the generation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. The specific genetic programs underlying the differentiation of mature neurons from their progenitors remain incompletely characterized, in part because of the difficulty in studying neuronal progenitor 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 multipotent neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on the properties of neuronal stem cells. While distinct stages of the olfactory lineage have been identified with a limited set of molecular markers, much remains to be learned about the genetic programs that both define and regulate olfactory neurogenesis during development and regeneration. To date, nothing is known about the transcriptional networks regulating the multipotent olfactory progenitors, the earliest cells in the lineage. Elucidation of these regulatory networks is critical for understanding how mature neuronal and non-neuronal cell types are generated from the adult tissue stem cell of the olfactory epithelium. In this application we propose to investigate the role of the transcription factor p63 - a member of the p53 family of tumor suppressors - in olfactory stem cell regulation. Through whole genome transcriptome profiling and genetic loss-of-function analysis, we recently discovered that p63 is a key regulator of olfactory stem cell self-renewal and differentiation in vivo, similar to its established role in other epithelial stem cells. Here we propose to investigate the cellular and molecular actions of p63 in the olfactory stem cell. Specifically, we will (1) determine the role of p63 in the choice between self-renewal and differentiation; (2) determine whether p63 and its related family member p53 interact to regulate olfactory stem cell dynamics; and (3) characterize the p63-dependent transcriptional network regulating the olfactory stem cell by identifying the downstream targets of p63. Together these investigations will illuminate the cellular and molecular mechanisms regulating olfactory stem cell maintenance, proliferation and differentiation. Moreover, our studies will provide a model for understanding the mechanisms regulating other neural stem cell types and lay the groundwork for the future development of treatments and therapeutics to ameliorate neural tissue damage and degeneration.

描述（由申请人提供）：神经系统中神经元多样性的产生需要多种细胞谱系的规范和分化。连续的发育程序控制单个神经元类型的产生、细胞迁移、轴突延伸，并最终控制功能性突触连接的形成。成熟神经元与其祖细胞分化的具体遗传程序仍未完全表征，部分原因是在其天然环境中研究神经元祖细胞很困难。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通过多能神经祖细胞的增殖和分化不断再生。这一特征使得嗅觉系统特别适合研究神经元干细胞的特性。虽然嗅觉谱系的不同阶段已经通过一组有限的分子标记被识别出来，但关于在发育和再生过程中定义和调节嗅觉神经发生的遗传程序还有很多东西需要了解。迄今为止，人们对调节多能嗅觉祖细胞（谱系中最早的细胞）的转录网络一无所知。阐明这些调节网络对于理解成熟的神经元和非神经元细胞类型是如何从嗅上皮的成体组织干细胞产生的至关重要。在本申请中，我们打算研究转录因子 p63（肿瘤抑制因子 p53 家族的成员）在嗅觉干细胞调节中的作用。通过全基因组转录组分析和遗传功能丧失分析，我们最近发现p63是体内嗅觉干细胞自我更新和分化的关键调节因子，类似于其在其他上皮干细胞中的既定作用。在这里，我们建议研究 p63 在嗅觉干细胞中的细胞和分子作用。具体来说，我们将（1）确定p63在自我更新和分化选择中的作用； (2)确定p63及其相关家族成员p53是否相互作用来调节嗅觉干细胞动力学； (3) 通过鉴定 p63 的下游靶标来表征调节嗅觉干细胞的 p63 依赖性转录网络。这些研究将共同​​阐明调节嗅觉干细胞维持、增殖和分化的细胞和分子机制。此外，我们的研究将为理解调节其他神经干细胞类型的机制提供一个模型，并为未来开发改善神经组织损伤和变性的治疗和疗法奠定基础。