Oncogenic Gene Regulatory Networks

致癌基因调控网络

• 批准号: 7346961
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7346961
• 关键词: Affect; Applications Grants; Characteristics; Computer Analysis; Conflict (Psychology); Dependency; Depth; Development; Event; Funding; Gene Activation; Gene Expression; Gene Expression Profile; Gene Order; Genes; Genome; Goals; Grant; Human; Human Development; Malignant Neoplasms; Measures; Methodology; Methods; Molecular Profiling; Mutation; Nature; Oncogenic; Pathway interactions; Pattern; Process; Proteins; RNA Interference; Regulation; Regulator Genes; Regulatory Element; Research; Sampling; Sequence Analysis; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; Study Section; TP53 gene; Time; Work; cell growth; computerized tools; falls; loss of function; malignant breast neoplasm; promoter

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实现对致癌信号通路和网络的性质的更深入和综合的理解。到目前为止，研究的重点是确定和表征各种致癌调控活动的直接目标，但缺乏对这些途径的全面和综合的看法。我们最近的工作开发了方法学，使用基因组规模的基因表达测量，结合先进的计算工具，对与各种致癌活动的行动相关的基因调控网络进行了更详细的了解。这项工作的重要性在于，这一组活动已被证明对正常的细胞生长控制至关重要；放松对RAS、Myc和Rb途径等活动的调控是癌症发展的核心。这项提案的具体目标旨在实现这一总体目标，包括通过分析基因组规模的表达模式来识别受各种致癌信号活动控制的基因调控网络。这将涉及进一步探索受RAS、Myc和E2Fs调控的通路，然后将扩展到其他重要的通路，包括Src、Ab1、P53和其他。我们还将应用新开发的方法进行基因表达分析，我们相信这些方法将有助于剖析信号通路的复杂性。然后，我们将利用这些致癌通路的特征来表征一系列人类癌症，以解除致癌信号通路的调控，作为重建与人类癌症发展相关的基因调控事件的一种方法。其他工作将致力于确定通路中的结构，根据启动子结构的特征对基因进行排序，从而提出共同的调节模块，以及通路中基因之间的功能关系。最后，我们将使用siRNA分子作为一种机制来剖析调控网络，确定功能关系和依赖关系。我们的目标是加深对这些基因表达网络的理解，重要的是，考虑到这些途径之间已经建立的关系，我们的目标不仅是定义这些活动的下游靶标，而且要对与途径激活相关的事件进行全面的描述。最终，这还将涉及通过了解一种途径的激活如何影响另一种途径来整合这些途径。