Molecular mechanisms of notch signaling in neoplasia

大量证据表明Notch基因家族在多种人类癌症中发挥作用，包括 淋巴系统、胰腺、乳腺和CMS等的肿瘤。但 Notch功能的病理生理机制仍然知之甚少。的基本假设 这一假设是Notch信号转导通路的失调驱动肿瘤转化 在转化状态的启动和维持中起着重要作用。这 转化活性是Notch的固有特性，并且Notch通过信号传导介导其作用。 复合物。 我的实验室已经开发出体外策略来研究哺乳动物Notch的作用机制， 细胞肿瘤转化的信号转导途径。本研究旨在 为了更好地理解Notch的分子本质以及Notch的激活如何颠覆 细胞的正常生理机能并解除生长控制。该提案的具体目标包括： Notch的结构与功能分析，Notch信号复合物的表征，细胞凋亡机制， Notch对细胞周期和基因表达的调控。这些研究的长期目标是 获得Notch活动如何转化细胞的全面了解，以有助于 癌症治疗的合理设计。

Substantial evidence has demonstrated a role for the Notch gene family in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CMS, among others. However, the pathophysiological mechanism of Notch function remains poorly understood. The underlying hypothesis of this proposal is that deregulation of the Notch signal transduction pathway drives the neoplastic conversion of cells, playing an important role in both the initiation and maintenance of the transformed state. This transforming activity is an intrinsic property of Notch and Notch mediates its effects through a signaling complex(s). My laboratory has developed in vitro strategies to study the mechanism of action of the mammalian Notch signal transduction pathway in the neoplastic transformation of cells. Research proposed herein is designed to seek a better understanding of the molecular nature of Notch and how activation of Notch subverts the normal physiology of the cell and deregulates growth controls. Specific aims for this proposal include; structure and function analysis of Notch, characterization of the Notch signaling complex, mechanism of cell cycle regulation and regulation of gene expression by Notch. The long-range goal for these studies is to obtain a comprehensive understanding of how Notch activity transforms cells in order to contribute to the rational design of cancer therapeutics.