Transcriptional Control of Terminal Differentiation

末端分化的转录控制

• 批准号: 6513443
• 负责人: DANIEL L KILPATRICK
• 金额: $ 26.28万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-08 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513443
• 关键词: Adenoviridae; Sindbis virus; antisense nucleic acid; apoptosis; chimeric proteins; developmental genetics; developmental neurobiology; genetic promoter element; granule cell; laboratory mouse; nerve /myelin protein; nerve stem cell; neurogenesis; neurogenetics; oligonucleotides; recombinant virus; transcription factor; transfection /expression vector; virus protein

DESCRIPTION (provided by applicant): The linkage between cell cycle exit and terminal differentiation represents a critical phase of cellular development. However, very little is known regarding the mechanisms functioning at the growth arrest/differentiation interface in neurons and other cell types. Such mechanisms are likely to play a vital role in not only the onset or establishment of terminal differentiation, but also in the maintenance of its normal irreversibility. Thus, elucidating the mechanisms operating at this critical developmental juncture is also likely to be importance in understanding the etiology and treatment of many forms of cancer. The long-term goal of this proposal is to determine how the events associated with growth arrest are mechanistically linked to transcriptional regulation of specific genes during onset of terminal differentiation and how transcription factors activating these promoters are themselves regulated by growth arrest signals. This proposal focuses on neurogenesis, during which arrest of neuroblasts leads to the "birth" of postmitotic neurons and the onset of terminal differentiation. This event is a major determinant of which neurons survive and ultimately form the complex wiring of the nervous system, and also is important in establishing the identities of specific neuronal sub-types. An underlying hypothesis is that the mechanisms linking growth arrest and differentiation in neurons are cell lineage-specific. A major goal is to characterize the basis for this neuron-specificity and, in particular, the nature of the regulatory transcription factors involved. These studies will help to reveal the mechanisms controlling neurogenesis during development as well as in the adult nervous system, and in this regard are relevant to potential therapies for neuro-degenerative diseases. Further, they are important for understanding tumorigenesis in general, including neoplasias of the nervous system.

描述（由申请人提供）：细胞周期退出和细胞周期退出之间的联系 终末分化代表细胞发育的关键阶段。 然而，人们对于其运作机制知之甚少。 神经元和其他细胞类型中的生长停滞/分化界面。这样的 机制可能不仅在发病或 终端差异化的建立，还在于维持其 正常的不可逆性。因此，阐明在此操作的机制 关键的发展关头也可能很重要 了解多种癌症的病因和治疗。长期来看 该提案的目标是确定与增长相关的事件如何 逮捕在机制上与特定的转录调控相关 终末分化开始期间的基因以及转录因子如何 激活这些启动子本身受到生长停滞信号的调节。 该提案的重点是神经发生，在此期间神经母细胞的停滞导致 有丝分裂后神经元的“诞生”和终末期的开始 差异化。该事件是神经元存活和存活的主要决定因素 最终形成神经系统的复杂线路，也很重要 确定特定神经元亚型的身份。底层的 假设是连接生长停滞和分化的机制 神经元具有细胞谱系特异性。主要目标是表征基础 对于这种神经元特异性，特别是调节的性质 涉及转录因子。这些研究将有助于揭示 发育过程中以及成人中控制神经发生的机制 神经系统，在这方面与潜在的治疗方法有关 神经退行性疾病。此外，它们对于理解也很重要 一般肿瘤发生，包括神经系统肿瘤。