High Throughput Protein-Protein Interaction Interrogation in Cancer

描述（由申请人提供）：埃默里分子相互作用功能基因组学中心（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，创新的HTS分析开发化学铅发现的生产记录，以及成熟的癌症基因组学挖掘，数据库和数据集成能力，寻求成为NCI癌症靶点发现和开发（CTDD）网络中的一个节点。癌症基因组计划（如癌症基因组图谱（TCGA））显示，各种肿瘤类型的基因组改变通常会导致重新连接的蛋白质-蛋白质相互作用网络，进而驱动肿瘤的发生和发展。因此，通过各种基因组学数据集确定癌蛋白和肿瘤抑制因子之间的突出PPI节点和网络，并验证它们在肿瘤发生和进展中的关键作用，有望揭示一类全新的基于PPI的癌症靶点，用于治疗开发。为了实现这一目标，我们建议利用我们已建立的高通量PPI技术，通过团队科学方法来查询癌症基因组学信息(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分析，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，以优先定位PPI，功能性PPI验证，以及跨网络数据共享和协作。我们的目标是通过建立和询问癌症PPI靶点空间来弥合巨大的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，这些技术可高度适应各种输出，我们打算在合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. PUBLIC HEALTH RELEVANCE: While current drug discovery is primarily focused on a single molecular target, such as a kinase or a transmembrane receptor, our project intends to target the interface between two proteins (protein-protein interactions) to disrupt the signaling networks that cancers rely on. Genomic alterations in cancer often lead to re-wired protein interaction networks. Interrogation of these cancer-associated protein-protein interactions with high throughput methods offers new opportunities for the discovery of novel therapeutics.