Mitogenesis Networks

有丝分裂信号网络项目的总体目标是开发高水平的统计和特定的物理化学模型，描述由ErbB受体和致癌K-ras激活的有丝分裂信号网络的关键特征。在过去的4年里，我们在开发各种细胞类型的ErbB家族有丝分裂信号网络模型方面取得了重大进展，包括描述各种ErbB家族成员表达增加影响的统计和动力学模型。在接下来的五年中，我们将扩展这些模型，包括由EGFR和K-Ras突变异型引起的有丝分裂信号网络，这些突变异型与中枢神经和呼吸系统人类癌症的不良预后直接相关。模型将在各种规模上进行开发和测试，包括体外细胞培养系统、小鼠异种移植和小鼠癌症模型。此外，由于我们目前的ICBP资助的一个试点项目的成功，我们将扩展这些模型来整合转录调控网络，提供一个更全局的、定量的细胞调控模型来响应致癌突变。

The overall goal of the Mitogenic Signaling Networks project is the development of high level statistical and specific physico-chemical models that describe key features of mitogenic signaling networks activated by ErbB receptors and by oncogenic K-ras. Over the past 4 years we have made significant progress in developing models of ErbB family mitogenic signaling networks in a variety of cell types, including statistical and kinetic models describing the effects of increased expression of various ErbB family members. Over the next five years we will extend these models to include mitogenic signaling networks resulting from mutant isoforms of EGFR and K-Ras that are directly associated with poor prognosis in human cancers of the central nervous and respiratory systems. Models will be developed and tested at a variety of scales, including in vitro cell culture systems, murine xenografts, and mouse cancer models. In addition, due to the success of a pilot project funded from our current ICBP, we will extend these models to integrate transcriptional regulatory networks, providing a more global, quantitative model of cellular regulation in response to oncogenic mutation. Since therapeutic resistance is one of the hallmarks of lung and brain tumors driven by mutant EGFR and mutant Ras, in the next phase of this project we will quantify and model signaling and transcriptional network alterations resulting from treatment with a variety of therapeutics, including classical chemotherapeutics, targeted therapeutics, and radiation. The goal of this project is to understand adaptation mechanisms used by tumor cells in developing therapeutic resistance in order to target these adaptive mechanisms to revert resistance. Quantitative models of mitogenic signaling network responses to therapeutics will be applied to human tumors to test their ability to predict responsiveness of human tumors to selected chemotherapeutic agents. This project will facilitate the integration of mitogenic signaling network models with DNA damage response models developed in Project 2, leading to more integrated models of cellular regulatory networks.