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.
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