Imaging Delta-Induced Activation of Notch

成像 Delta 诱导的 Notch 激活

• 批准号: 7386757
• 负责人: James Tucker Nichols
• 金额: $ 1.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386757
• 关键词: Alzheimer' s Disease; Cell Communication; Cell Nucleus; Cell surface; Cells; Characteristics; Coculture Techniques; Condition; Confocal Microscopy; D Cells; Defect; Development; Drosophila genus; Endocytosis; Event; Extracellular Domain; Gene Targeting; Genetic Transcription; Image; Length; Ligands; Malignant Neoplasms; Mammalian Cell; Mammals; Modeling; Molecular; Movement; Numbers; Play; Process; Proteolysis; Research Training; Role; Series; Signal Transduction; Stroke; System; base; cell type; human disease; insight; notch protein

DESCRIPTION (provided by applicant): Notch signaling is a highly conserved cell communication system that regulates a wide variety of cell types throughout development and into adulthood. Defects in Notch signal transduction have been implicated in a number of human disease states including cancer, stroke, and Alzheimer's disease, underscoring the importance of understanding the basic mechanisms of Notch signal transduction. Cell-surface Notch receptors, following engagement with cell-surface ligands, undergo a series of proteolytic cleavage events which release the intracellular domain of Notch. This proteolytic fragment translocates to the nucleus of the signal receiving cell where it directly regulates transcription of Notch target genes. Based on studies in Drosophila, a model for Notch signaling has been proposed in which the ligand-signaling cell plays an active role in Notch activation beyond ligand presentation. These models propose that during signal transduction the ligand cell actively removes the Notch extracellular domain through the poorly understood phenomenon of trans-endocytosis. This proposal aims to determine if trans-endocytosis is a characteristic of ligand- induced Notch signaling in mammals. To this end, a coculture system that can be examined by confocal microscopy has been developed. This coculture paradigm will allow characterization of the specifics of Notch transfer to Delta cells, providing insight into the molecular mechanism of trans-endocytosis and its relevance to Notch signaling.

描述（由申请人提供）：Notch信号传导是一种高度保守的细胞通讯系统，在整个发育过程中调节各种细胞类型并进入成年期。Notch信号转导的缺陷与许多人类疾病状态有关，包括癌症，中风和阿尔茨海默病，强调了理解Notch信号转导基本机制的重要性。细胞表面Notch受体在与细胞表面配体接合后，经历一系列蛋白水解切割事件，其释放Notch的细胞内结构域。该蛋白水解片段易位到信号接收细胞的细胞核，在那里它直接调节Notch靶基因的转录。基于在果蝇中的研究，已经提出了Notch信号传导的模型，其中配体信号传导细胞在Notch激活中发挥积极作用，而不是配体呈递。这些模型提出，在信号转导过程中，配体细胞通过知之甚少的反式内吞现象主动去除Notch细胞外结构域。该提议旨在确定反式内吞作用是否是哺乳动物中配体诱导的Notch信号传导的特征。为此，共培养系统，可以通过共聚焦显微镜检查已经开发出来。这种共培养模式将允许表征Notch转移到Delta细胞的特异性，从而深入了解反式内吞作用的分子机制及其与Notch信号传导的相关性。