RCDL 2006 Suzdal Oct A Prototype of the HumanVirus Interact ome Resource (HVIR) Tax1 Protein B Binds to Interacts with Co-localizes with Co-purifies with Forms a complex with Alex Pothen M. Zubair Kurt Maly Chris Osgood John Semmes RCDL 2006 Suzdal Oct Viruses in the News HIV, SARS, Avian Flu, Human flu pandemics A virus conjectured to be cause of mammalian extinctions in the Pleistocene Viral proteins interacting with human proteins are responsible for infection and transmission; targets for therapies Currently no automated tools to mine published viral-human protein interactions RCDL 2006 Suzdal Oct Coping with Growing Proteomic Information Recent advances in protein science High throughput experimental methodologies: Yeast 2-hybrid system, Tagged affinity purification, etc. On-line literature and protein interactions databases growing rapidly (>16 Million abstracts in PubMed) Need for automated tools to aggregate data, process it, and present it visually in biologically meaningful ways Need standards for representing data, and tools that support interoperable databases RCDL 2006 Suzdal Oct 5 The HVIR Framework Viral-human protein interactions mined from the literature, e.g., PubMed Human interactome from curated databases, e.g., Human Protein Reference Database (HPRD) Integrate the data into a repository, HVIR Standards for representing protein interactions Unique IDs from International Protein Index Semi-automated curation Regularly harvest new data from literature, databases Build tools to be interoperable RCDL 2006 Suzdal Oct The HVIR Framework Organize interactions network in biologically meaningful ways Visualize the network for interactive exploration Make biological inferences, guide further expts. Initially create this tool for the Human T-cell Lukemia virus (HTLV-1), its protein, Tax RCDL 2006 Suzdal Oct 8 9 10 Four Objectives of HVIR Tools for creating and sharing protein interaction data Tools for processing and organizing interaction networks Tools for validating interactions Tools for evaluating effectiveness and scalability of the tools above RCDL 2006 Suzdal Oct Four Objectives of HVIR Creating and sharing interactions: literature mining, standards for representing interactions data, protocols for harvesting data from multiple databases (Open Architecture Initiative) Processing interactome networks: clustering using multiple criteria, visualization tools for exploring networks Validating content: assign confidence values using probabilistic models, curate ones with low confidence Evaluate effectiveness: focus groups of users evaluate how HVIR guides experimentation RCDL 2006 Suzdal Oct Identifying proteins in Tax complex (Durkin, Semmes) S-Tax-GFP kDa S-Tax-GFP S-GFP PR (DNA-PK) Silver stain PR PR PR PR PR PR PR kDa PR S-GFP S-Tax-GFP S-GFP B A RCDL 2006 Suzdal Oct Tax co-localizes with activated DNA-PK (Durkin, Semmes) STaxGFP Nuclear stain DNA-PK p-T2609 merge RCDL 2006 Suzdal Oct Summary of Work Designed HVIR to provide virologists with data on protein interaction networks Four major sets of tools: creating interaction data, processing it, validating it, and evaluating effectiveness. Built a prototype for the HTLV-1 virus in collaboration with virologists and demonstrated it to them. The Tax interactome now known to include 82 proteins vs. 8 when we began. Seeking funding to build and extend HVIR. RCDL 2006 Suzdal Oct Future work Detailed study of the Tax interactome to generate predictions and validate utility of HVIR. Build HVIR and make it available for use by biologists. Employ a second virus, cytomegalovirus (CMV), with a larger set of proteins to study scalability (Julie Kerry, EVMS). Promote standards for data representation and interoperable protocols for data harvesting. RCDL 2006 Suzdal Oct HVIR Educational Impact Emad Ramadan, Mahmoud Abu-Elela, Khaled Ibrahim PhD students in Computer Science Sarah Durkin PhD student in Microbiology and Molecular Cell Biology, EVMS Praveen Namburi, Sheetal Jagwani, Bhavana Thapde Masters students in Computer Science Hunter Baldwin Masters student in Biology RCDL 2006 Suzdal Oct Publications A Prototype of the Human Virus Interactome Resource (HVIR) Proceedings of the 8th Russian National Conference on Digital Libraries, 2006 SIAM Conference on Life Sciences, Raleigh, Aug International Symposium on Bioinformatics Research and Applications, Atlanta, 2007 (Program committee) Paper in Retrovirology, in preparation RCDL 2006 Suzdal Oct Funding NSF An Interoperable Human Virus Interactome Resource, Biol. Databases and Informatics program, submitted July 2006, PI: Kurt Maly $1,256,054 for 4 years begin. Jan. 1, 2007 NIH Have contacted program officers and NIH researchers formerly at ODU Plan Fall 2006 or Spring 2007 submission RCDL 2006 Suzdal Oct Human-Virus Interactome Resource Team Kurt Maly, M. Zubair (Digital Libraries) Computer Science, ODU Chris Osgood (Genomics, Nanobiology) Biological Sciences, ODU John Semmes (Proteomics, Virology) Microbiology and Molecular Cell Biology, Eastern Virginia Medical School Alex Pothen ( Scientific Computing, Bioinformatics ) Computer Science, ODU RCDL 2006 Suzdal Oct HVIR Input form RCDL 2006 Suzdal Oct Tax interactors RCDL 2006 Suzdal Oct RCDL 2006 Suzdal Oct Second neighbors of Tax RCDL 2006 Suzdal Oct Local network of selected protein RCDL 2006 Suzdal Oct FR Layout, selected proteins RCDL 2006 Suzdal Oct A subnetwork of selected proteins RCDL 2006 Suzdal Oct A subnetwork of sel. proteins RCDL 2006 Suzdal Oct Incremental Navigation RCDL 2006 Suzdal Oct Incremental Navigation RCDL 2006 Suzdal Oct Shortest path from Tax RCDL 2006 Suzdal Oct Zooming in on a subnetwork RCDL 2006 Suzdal Oct Early version of Tax network Tax1 DNA-PK CHK2 MAD1 53BP1 RelA ATF4 ATF5 NEMO RCDL 2006 Suzdal Oct Current version of Tax network N = 82 RCDL 2006 Suzdal Oct HVIR (Human-Virus Interactome Resource) CS Alex Pothen Kurt Maly M Zubair Chris Osgood John Semmes Biol EVMS