Control of Cell Proliferation and Differentiation in the Developing Retina

视网膜发育中细胞增殖和分化的控制

• 批准号: 7178326
• 负责人: WEI DU
• 金额: $ 5.59万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178326
• 关键词: Control; Cell; Proliferation; Differentiation; Developing

DESCRIPTION (provided by applicant): The long term objective of this research is to elucidate the molecular mechanisms by which cell proliferation or differentiation is controlled in animal development. Specifically, the research in this grant will use the Drosophila developing retina as a model system to investigate the mechanisms by which developmental signaling pathways such as Notch and cell intrinsic transcription factors such as atonal and daughterless interact to control cell proliferation and differentiation. Atonal is a bHLH family of transcription factor that is required for the initiation of photoreceptor cell differentiation. The induction of atonal in the developing eye requires Notch signaling, a conserved developmental pathway that has diverse roles in normal development. Notch signaling has also been implicated in regulating the cell cycle, however activation of Notch signaling will induce cell proliferation in some cell types while induce cell cycle arrest and differentiation in others. The mechanisms by which Notch signaling leads to cell proliferation or cell cycle arrest in distinct cell types remains elusive. The Drosophila developing retina provides a unique developmental system that is ideally suited for this investigation because of the well-characterize patterns of cell proliferation and the developmental signaling and because of the ease of generating loss or gain of function cell clones that can be precisely identified during development. Furthermore, the eye-specific enhancers for three of Notch's cell proliferation and differentiation targets have been identified. In this grant, we use these reagents to investigate the mechanism by which Notch signaling regulates cell proliferation in the Drosophila developing retina. Specifically, we propose to (1) determine the role of Notch signaling in cell cycle regulation and in the regulation of cyclin E and Dacapo; (2) determine the role of atonal and daughterless in coordinating cell cycle arrest with cell differentiation; and (3) determine the mechanism by which Notch and other developmental signaling pathways regulate atonal expression and cell proliferation or differentiation. Since the Notch pathway is conserved in mammalian systems and is often deregulated in human diseases including cancers, the proposed studies will provide significant new insight into the roles of Notch signaling in developmentally regulated cell proliferation as well as in human cancers.

描述（由申请人提供）：本研究的长期目标是阐明动物发育中控制细胞增殖或分化的分子机制。具体而言，该研究将使用果蝇发育中的视网膜作为模型系统，以研究Notch等发育信号通路和无调和无子体等细胞内在转录因子相互作用控制细胞增殖和分化的机制。Atonal是一个bHLH家族的转录因子，是感光细胞分化的起始所必需的。在发育中的眼睛中无调的诱导需要Notch信号传导，这是一种在正常发育中具有不同作用的保守发育途径。Notch信号传导也涉及调节细胞周期，然而Notch信号传导的激活将在一些细胞类型中诱导细胞增殖，而在其他细胞类型中诱导细胞周期停滞和分化。Notch信号传导导致不同细胞类型中的细胞增殖或细胞周期停滞的机制仍然难以捉摸。果蝇发育中的视网膜提供了一个独特的发育系统，该系统非常适合于本研究，因为细胞增殖和发育信号的良好表征模式，并且因为容易产生在发育期间可以精确识别的功能细胞克隆的丧失或获得。此外，已经鉴定了三种Notch细胞增殖和分化靶点的眼睛特异性增强子。在这项资助中，我们使用这些试剂来研究Notch信号调节果蝇发育视网膜中细胞增殖的机制。具体而言，我们建议（1）确定Notch信号在细胞周期调控和细胞周期蛋白E和Dacapo的调节中的作用;（2）确定无调和无子代在协调细胞周期停滞与细胞分化中的作用;（3）确定Notch和其他发育信号通路调节无调表达和细胞增殖或分化的机制。由于Notch通路在哺乳动物系统中是保守的，并且在包括癌症在内的人类疾病中经常被解除调节，因此拟议的研究将为Notch信号传导在发育调节的细胞增殖以及人类癌症中的作用提供重要的新见解。