itNETZ: Integrative and Translational Network-based Cellular Signature Analyzer

描述（由申请人提供）：迫切需要开发系统平台，以应对集成网络蜂窝签名库（LINCS）计划快速发展所带来的挑战和机遇。LINCS项目进行跨领域高通量分析，并开发针对各种干扰剂和候选药物生成的信息分子活性和细胞特征特征的综合计算分析。 拟议的研究的主要目标是通过开发一个面向签名的软件平台，集成和翻译的基于网络的蜂窝签名分析仪（itNETZ），以满足需求。 系统的工作流程为：1）识别疾病和药物特异性分子和细胞特征，2）揭示这些特征的组分之间的机制关联，并将它们描绘为信号传导和调节网络，3）通过数学模型呈现这些网络的动力学，4）构建基于网络的分子和细胞特征，5）发现细胞系和疾病之间的共同特征和网络，6）建立和维护治疗反应的日益增长的结果知识的公共资源，以及7）促进研究团体查询感兴趣的特征，探索特征之间的相关性，并产生假设。 该系统将实现以下功能：第一，用于处理细胞图像、Luminex基因组学数据、转录组测序数据以及用于对磷蛋白信号通路进行建模的基本分析和发现工具包;第二，用于将基因组学和蛋白质组学映射到细胞表型的数据集成和挖掘工具包，用于在由不同抑制剂处理的细胞系上鉴定核心途径签名和药物诱导的途径签名改变，以及用于构建药物激酶组景观。itNETZ系统包括加载输入、分析图像、处理基因组学和蛋白质组学数据、将输出导出到关系数据库、整合和挖掘数据以及生成感兴趣的基于网络的细胞签名的管道。基于XML的协议将用于数据交换。 公共卫生相关性：本项目将通过了解药物的作用机制，以及不同治疗条件下的网络签名，为公共卫生做出实质性贡献。更重要的是，该项目的完成将有助于回答与药物靶向特征相关的一些关键问题。这样的理解将反过来推进我们在肿瘤生物学方面的知识，并为未来的新治疗开辟可能性。

DESCRIPTION (provided by applicant): There is an urgent need to develop systematic platforms to address the challenges and opportunities brought forth by the fast progresses of the Library of Integrated Network-Based Cellular Signatures (LINCS) program. The LINCS program performs cross-cutting high-throughput assays and develops integrative computational analysis of informative molecular activity and cellular feature signatures generated in response to a variety of perturbing agents and drug candidates. The primary goal of the proposed study is to address the needs by developing a signature-oriented software platform, the Integrative and Translational Network-based Cellular Signature Analyzer (itNETZ). The working flow of the system is: 1) to identify disease- and drug-specific molecular and cellular features, 2) to reveal the mechanismistic associations between components of such features and delineate them as signaling and regulating networks, 3) to present the dynamics of such networks by mathematical models, 4) to construct network-based molecular and cellular signatures, 5) to discover common signatures and networks across cell lines and diseases, 6) to establish and maintain a public resource of the increasing resultant knowledge of therapeutic responses, and 7) to facilitate the research community on querying signatures of interests, exploring correlations among signatures, and generating hypotheses. This system will enable the following functions: first, the basic analysis and discovery toolkits for processing cellular images, Luminex genomics data, transcriptome sequencing data, and for modeling phosphoproteins signaling pathway; and second, data integration and mining toolkits for mapping genomics and proteomics to cellular phenotypes, for core pathway signature identification on cell lines treated by different inhibitors and drug-induced pathway signature alterations, and for constructing drug kinome landscapes. The itNETZ system comprises pipelines that load input, analyze images, process genomics and proteomics data, export outputs into a relational database, integrate and mine the data, and generate network-based cellular signatures of interest. XML-based protocols will be used for data exchanging. PUBLIC HEALTH RELEVANCE: This project will be a substantial contribution to the public health by understanding the mechanism of drugs, and network signature under different treatment conditions. More importantly, the completion of this project will help to answer some critical questions related to drug target signatures. Such understanding will in turn advance our knowledge in tumor biology and open up the possibility of novel treatments in the future.