Notch Signaling in Mammary Development and Tumorigenesis

描述(申请人提供)：Noch信号定义了控制细胞命运获取的基本细胞信号通路。Notch信号控制着非常广泛的组织的发育，这种信号的实验调制导致细胞命运在包括人类在内的多细胞生物体的整个发育过程中发生变化。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Notch在肿瘤发生中的直接参与，我们希望探讨Notch信号在肿瘤中的调节作用及其对特定细胞系命运的影响。我们将把注意力集中在乳腺上，这是一种具有良好发育特征的组织，以及已建立的小鼠癌症模型。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。所提出的目标将在转基因小鼠的帮助下检查Notch信号调制在小鼠乳腺上皮中的后果。我们希望这些研究将为分析Notch信号在乳腺组织中的作用提供坚实的基础，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，我们还将利用细胞培养系统研究Notch在增殖事件中的作用。

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.