Many complex human diseases (e.g. cancer, diabetes, schizophrenia etc.) have correspondingly complex, polygenic genotypes that initiate and sustain disease progression. Despite significant progress over the past few decades identifying genes critical to mediating phenotype, our understanding of the functional basis of molecular phenotype for complex diseases is insufficient. Signaling pathways that consist of a few proteins interacting in a serial fashion oversimplify and provide inadequate models for the behavior mediated by multiple interacting gene products. Partly revealed by rigorous studies of increasingly well-annotated protein-protein interaction (PPI) networks, it has become clear that many of the proteins in these canonical signaling pathways engage in "crosstalk" with, and are modulated by, an ontologically diverse set of additional proteins, where this crosstalk is frequently mediated in a tissue and/or disease specific manner. We propose to develop and deliver an integrated suite of software tools to the academic and commercial research community to fulfill the unmet demand for quantitative PPI network analysis that can drive practical translational research and validation. The tool DiseaseNet Finder will search for and score candidate disease sub- networks within global PPI networks. It will permit integration of multiple high- dimensional -omic types (GWAS, SNP, CNV, proteomic, miRNA etc.) with PPI networks and include classification tools. Novel aspects of the software include: combinatorial scoring, multi data type integration, node and edge prediction tools, with end-point classification and quantitative scoring seamlessly implemented through graphical user interfaces.
Public Health Relevance: Complex diseases include the contributions of many genes interacting with the environment. Enhanced computational research tools to discover biomarkers and understand complex disease mechanisms are needed to integrate the various types of genomic and proteomics data that are accumulating. This will permit a more rapid development of personalized medicine.
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