Programs of Gene Expression in Olfactory Neurogenesis

嗅觉神经发生中的基因表达程序

• 批准号: 8663581
• 负责人: JOHN J. NGAI
• 金额: $ 34.35万
• 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/8663581
• 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特化和分化。连续的发育程序控制单个神经元类型的产生、细胞迁移、轴突延伸以及最终功能性突触连接的形成。成熟神经元从其祖细胞分化的特定遗传程序仍然不完全表征，部分原因是在其天然环境中研究神经元祖细胞的困难。在脊椎动物的嗅觉系统中，初级感觉神经元通过多能神经祖细胞的增殖和分化在整个成年期不断再生。这一特征使得嗅觉系统特别适合于神经干细胞特性的研究。虽然嗅觉谱系的不同阶段已经用有限的一组分子标记物确定，但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仍有待了解。迄今为止，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。阐明这些调控网络是至关重要的，了解如何成熟的神经元和非神经元细胞类型产生的成体组织干细胞的嗅上皮。在这个应用程序中，我们建议调查的作用，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。通过全基因组转录组分析和遗传功能缺失分析，我们最近发现，p63是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，我们建议调查的细胞和分子作用的p63在嗅觉干细胞。具体而言，我们将（1）确定p63在自我更新和分化之间的选择中的作用;（2）确定p63及其相关家族成员p53是否相互作用以调节嗅觉干细胞动力学;（3）通过识别p63的下游靶点来表征调节嗅觉干细胞的p63依赖性转录网络。这些研究将阐明嗅觉干细胞维持、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。