Notch Signaling in Mammary Development and Tumorigenesis

描述（由申请人提供）：Notch信号传导定义了控制细胞命运获得的基本细胞信号传导途径。Notch信号控制非常广谱的组织的发育，并且这种信号的实验性调节导致在包括人在内的多细胞生物体的整个发育过程中细胞命运的改变。鉴于Notch信号的多效性及其在控制细胞发育状态中的效力，以及已确立的Notch直接参与致癌作用，我们希望探索Notch信号调节在肿瘤中的结果及其影响特定细胞谱系命运的潜力。我们将把注意力集中在乳腺，一个具有良好特征的发育概况以及建立小鼠癌症模型的组织。我们的工作假设是Notch信号活性的变化将导致细胞命运的变化，包括特定致癌条件的命运。提出的目标将检查Notch信号调制的后果，在小鼠乳腺上皮细胞的帮助下，转基因小鼠。我们希望这些研究将提供一个坚实的基础，以分析Notch信号在乳腺组织中的作用，包括这些信号在乳腺肿瘤的发生和维持中的参与，以及评估这些信号影响肿瘤发生动力学的能力。为了补充我们对Notch信号如何影响肿瘤发生的理解，我们还将使用细胞培养系统研究Notch在增殖事件中的参与。

DESCRIPTION (provided by applicant): Notch signaling defines a fundamental cell signaling pathway controlling cell fate acquisition. Notch signals control the development of a very broad spectrum of tissues and experimental modulation of such signals results in cell fate changes throughout the development of multicellular organisms including man. Given the pleiotropy of Notch signals and their potency in controlling the developmental state of cells, as well as the established direct involvement of Notch in carcinogenesis, we wish to explore the consequences of Notch signal modulation in tumors and its potential to influence the fate of specific cell lineages. We will focus our attention to the mammary gland, a tissue with a well characterized developmental profile as well as established mouse cancer models. Our working hypothesis is that changes in Notch signaling activity will result in changes in cell fates, including the fate of specific oncogenic conditions. The aims proposed will examine the consequences of Notch signal modulation in the mouse mammary epithelium with the help of transgenic mice. We expect that these studies will provide a firm basis to analyze the action of Notch signals in mammary tissue, including the involvement of these signals in both the onset and maintenance of mammary tumors as well as evaluate the capacity of those signals to influence the kinetics of oncogenesis. In order to supplement our understanding of how Notch signaling influences oncogenesis, we will also study the involvement of Notch in proliferative events using cell culture systems.