Application of Technologies for Interactome Network Analyses of Cancer Mutations

癌症突变相互作用组网络分析技术的应用

• 批准号: 7632259
• 负责人: Marc Vidal
• 金额: $ 60.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632259
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Address; Alleles; Amino Acids; Attention; Biological; Biological Process; Cancer Etiology; Cells; Classification; Complex; DNA-Protein Interaction; Data Set; Development; Disease; Drug effect disorder; Generations; Genes; Goals; Human; Human Genome; Light; Malignant Neoplasms; Maps; Mediating; Medicine; Modeling; Molecular; Molecular Biology; Molecular Models; Molecular Profiling; Mutate; Mutation; Oncogenes; Pathogenesis; Property; Proteins; Proteome; Proteomics; System; Systems Analysis; Systems Biology; Technology; Time; Tumor Suppressor Genes; cancer genome; cost; functional genomics; genome sequencing; genome-wide; in vivo; innovative technologies; interest; molecular modeling; neoplastic cell; network models; new technology; novel; novel therapeutics; predictive modeling; protein protein interaction; research study; success; tumorigenesis

DESCRIPTION (provided by applicant): The molecular mechanisms underlying cancer have been mainly studied one or a few "cancer genes" at-a-time. However, it is thought that combinations of mutated or aberrantly expressed tumor suppressor- and oncogenes may be responsible for advancing cells through most steps of tumorigenesis. Many cancer causing mutations are disrupting interactions and these alterations are often directly related to the mechanism of pathogenesis. Thus, altered protein-protein interactions may directly point to a mechanism for cancerogenesis. More importantly, since it is becoming increasingly clear that genes and their products interact in complex biological networks with local and global properties, it is possible that perturbations of these networks contribute to cancer formation. We propose that a further understanding of the mechanisms involved in cancer, and the development of new therapeutic strategies, can be gained by i) studying genes and their products in the context of the molecular networks in which they function, and ii) investigating how such networks are altered in tumor cells compared to their unaffected counterparts. In addition to the information available from several drafts of the human genome sequence, genome- wide experimental strategies have been developed that will help us understand the effects of cancer mutations in the context of molecular networks: i) protein-protein and DNA-protein interaction networks or "interactome" networks are being mapped at an increasing pace, producing datasets with ever increasing quality and decreasing costs, and ii) large numbers of cancer-associated mutations are being discovered in the context of the human cancer genome project. Here we propose to develop a genome-wide application for a new technology platform that we have recently initiated to systematically study the effects of cancer-associated mutations on the physical and functional interactions mediated by the products encoded by cancer genes in the context of global interactome models. Our specific aims are to apply our experimental and computational technology platforms to: i) clone large numbers of cancer-associated missense or single amino acid change (SAC) alleles, ii) identify and characterize the interaction properties of large numbers of SAC alleles, iii) analyze the effects of SAC alleles on the local and global properties of interactome networks.

描述（由申请人提供）：主要研究了一个或几个“癌症基因”的分子机制。但是，人们认为突变或异常表达的肿瘤抑制和肿瘤的组合可能是通过肿瘤发生的大多数步骤来推进细胞的原因。许多引起突变的癌症正在破坏相互作用，这些改变通常与发病机理的机理直接相关。因此，改变的蛋白质蛋白质相互作用可能直接指向癌发生的机制。更重要的是，由于越来越清楚的是，基因及其产物与局部和全球性质的复杂生物网络相互作用，因此这些网络的扰动可能会导致癌症形成。我们建议，可以进一步了解涉及癌症的机制以及新的治疗策略的发展，可以通过i）在其起作用的分子网络的背景下研究基因及其产物，ii）研究了与未伴有的抗抗酸剂相比，研究肿瘤细胞中这种网络的变化是如何改变的。除了从人类基因组序列的几种草稿中获得的信息外，基因组广泛的实验策略还将有助于我们了解分子网络中癌症突变的影响：i）蛋白质 - 蛋白质 - 蛋白质相互作用网络和“相互作用组”网络的质量越来越多的成本，并逐步映射到较大的成本，并逐步映射出巨大的成本，并降低了癌症，并且II）且II），II），并在II中生成II）在人类癌症基因组项目的背景下。在这里，我们建议为新技术平台开发全基因组应用，我们最近启动了该应用程序，以系统地研究癌症相关突变对在全球相互作用模型背景下由癌症基因编码的产物介导的物理和功能相互作用的影响。我们的具体目的是将我们的实验和计算技术平台应用于：i）克隆大量与癌症相关的错义或单个氨基酸变化（SAC）等位基因，ii）识别和表征大量SAC等位基因的相互作用，分析SAC等位基因对相互作用网络的局部和全球属性的影响。