High Throughput Protein-Protein Interaction Interrogation in Cancer

描述（申请人提供）：埃默里功能基因组学分子相互作用中心（MicFG），凭借其在蛋白质-蛋白质相互作用（PPI）研究的高通量技术方面的专业知识，创新HTS检测开发化学铅发现的生产记录，以及经过验证的癌症基因组学挖掘，数据库和数据集成能力，NCI癌症靶标发现和开发（CTDD）网络的一个节点。如癌症基因组学计划（如癌症基因组图谱（TCGA））所揭示的，各种肿瘤类型中的基因组改变通常会导致重新连接蛋白质-蛋白质相互作用网络，从而驱动肿瘤的发生和进展。因此，通过各种基因组学数据集以及验证它们在肿瘤发生和进展中的关键作用，在癌蛋白和肿瘤抑制因子中识别出突出的PPI节点和网络，有望揭示出一类全新的基于PPI的癌症治疗靶点。为了实现这一目标，我们建议利用我们建立的高通量PPI技术，通过团队科学方法来询问癌症基因组学信息，（i）基于TCGA和其他基因组数据集快速建立选定癌症类型的致癌PPI网络，（ii）验证关键PPI节点或枢纽在肿瘤发生和进展中的功能作用，（iii）开发关键肿瘤相关PPI的HTS测定，以丰富NCI和药物发现领域的治疗靶点管道，以及（iv）利用我们的信息学能力进行基因组学数据挖掘，以进行优先PPI作图，功能PPI验证，以及跨网络的数据共享和协作。我们的目标是通过建立和询问癌症PPI靶空间来弥合巨大基因组数据集和治疗发现之间的差距。凭借我们的PPI专业知识和最先进的高通量技术，这些技术高度适应各种输出，我们打算在协作跨网络项目中发挥积极的协同作用。

DESCRIPTION (provided by applicant): The Emory Molecular Interaction Center for Functional Genomics (MicFG), with its expertise in high throughput technologies for the study of protein-protein interactions (PPI), productive track record of innovative HTS assay development for chemical lead discovery, and proven cancer genomics mining, database, and data integration capabilities, seeks to become a node in the NCI Cancer Target Discovery and Development (CTDD) Network. Genomic alterations in various tumor types, as revealed by cancer genomics initiatives such as The Cancer Genome Atlas (TCGA), often lead to re-wired protein-protein interaction networks, which in turn drive tumor initiation and progression. Thus, identifying prominent PPI nodes and networks among oncoproteins and tumor suppressors as enriched by various genomics datasets and the validation of their critical roles in tumorigenesis and progression are expected to reveal an entirely new class of PPI-based cancer targets for therapeutic development. To achieve this goal, we propose to utilize our established high throughput PPI technologies to interrogate cancer genomics information through a team science approach (i) to rapidly establish oncogenic PPI networks of selected cancer types based on TCGA and other genomic datasets, (ii) to validate functional roles of key PPI nodes or hubs in tumorigenesis and progression, (iii) to develop HTS assays for critical tumor-associated PPIs to enrich the therapeutic target pipeline of the NCI and the drug discovery field, and (iv) to leverage our informatics capability for genomics data mining for prioritized PPI mapping, functional PPI validation, and trans-network data sharing and collaboration. We aim to bridge the gap between vast genomic datasets and therapeutic discovery by establishing and interrogating the cancer PPI target space. With our PPI expertise and state-of-the-art high throughput technologies, which are highly adaptable to a variety of outputs, we intend to function as an active, synergistic member in collaborative trans- Network projects.