Oncogenic Gene Regulatory Networks

致癌基因调控网络

基本信息

批准号：
7539157
负责人：
JOSEPH R NEVINS
金额：
$ 28.41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2009-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the work described in this proposal is to achieve a deeper and integrated understanding of the nature of oncogenic signaling pathways and networks. Studies to date have focused on the identification and characterization of immediate targets for various oncogenic regulatory activities but fall short of developing a comprehensive and integrated view of the pathways. Our recent work has developed methodologies, using genome-scale measures of gene expression, together with advanced computational tools, to develop a more detailed understanding of the gene regulatory networks associated with the action of various oncogenic activities. The importance of the work lies in the fact that this group of activities have been shown to be critical for normal cellular growth control; deregulation of activities such as Ras, Myc, and the Rb pathway are central to the development of cancer. The specific objectives of this proposal, that will aim to accomplish this overall goal, include the identification of gene regulatory networks controlled by the action of various oncogenic signaling activities through an analysis of genome-scale expression patterns. This will involve work to further explore pathways regulated by Ras, Myc, and E2Fs and then will be extended to other important pathways including Src, Abl, p53 and others. We will also apply newly developed methods for gene expression analysis that we believe will help to dissect the complexity of the signaling pathways. We will then employ these signatures of oncogenic pathways to characterize a series of human cancers for deregulation of the oncogenic signaling pathways as an approach to reconstructing the gene regulatory events associated with the development of human cancer. Additional work will aim to identify structure within the pathways, ordering genes with respect to characteristics of promoter structure suggesting common regulatory modules, as well as functional relationships between genes in the pathways. Finally, we will employ siRNA molecules as a mechanism to dissect the regulatory networks, identifying functional relationships and dependencies. Our goal is to develop a deeper understanding of these gene expression networks and importantly, given the established relationships between many of these pathways, we aim to not just define the downstream targets of these activities but to develop a comprehensive picture of the events associated with the activation of the pathway. Ultimately, this will also involve an integration of the pathways by understanding how the activation of one pathway affects another.

描述（由申请人提供）：本提案中描述的工作的总体目标是对致癌信号通路和网络的性质进行更深入的综合理解。迄今为止的研究集中在识别和表征各种致癌调节活动的近期靶标，但没有发展途径的全面和综合视图。我们最近的工作开发了方法，使用基因组尺度的基因表达度量以及先进的计算工具，以对与各种致癌活动的作用相关的基因调节网络有了更详细的了解。这项工作的重要性在于，事实证明，这组活动对于正常的细胞生长控制至关重要。 RAS，MYC和RB途径等活动的放松管制对于癌症的发展至关重要。该提案的特定目标，旨在实现这一总体目标，包括通过分析基因组尺度表达模式来识别通过各种致癌信号活动控制的基因调节网络。这将涉及进一步探索由RAS，MYC和E2FS调节的途径，然后将其扩展到其他重要途径，包括SRC，ABL，P53等。我们还将应用新开发的方法进行基因表达分析，我们认为这将有助于剖析信号传导途径的复杂性。然后，我们将采用这些致癌途径的特征来表征一系列人类癌症，以消除致癌信号传导途径，以此作为重建与人类癌症发展相关的基因调节事件的方法。其他工作将旨在识别途径内的结构，从而对启动子结构的特征进行订购基因，这些启动子结构表明了常见的调节模块以及途径中基因之间的功能关系。最后，我们将利用siRNA分子作为一种机制来剖析调节网络，识别功能关系和依赖性。我们的目标是对这些基因表达网络有更深入的了解，重要的是，考虑到许多这些途径之间的既定关系，我们的目标不仅是定义这些活动的下游目标，而且要对与途径激活相关的事件进行全面了解。最终，这也将通过了解一个途径的激活如何影响另一个途径来涉及途径的整合。