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Final Consortium Meeting, Barcelona, 27 th and 28 th June 2007

Deliverables – Publications citing Infobiomed. Published 1. Critchley HO, Robertson KA, Forster T, Henderson TA, Williams AR, Ghazal P. 2006. Gene expression profiling of mid to late secretory phase endometrial biopsies from women with menstrual complaint. Am J Obstet Gynecol 195: 406 e1-16

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Final Consortium Meeting, Barcelona, 27 th and 28 th June 2007

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  1. Deliverables – Publications citing Infobiomed • Published • 1. Critchley HO, Robertson KA, Forster T, Henderson TA, Williams AR, Ghazal P. 2006. Gene expression profiling of mid to late secretory phase endometrial biopsies from women with menstrual complaint. Am J Obstet Gynecol 195: 406 e1-16 • Grimes GR, Moodie S, Beattie JS, Craigon M, Dickinson P, Forster T, Livingston AD, Mewissen M, Robertson KA, Ross AJ, Sing G, Ghazal P. 2005. GPX-Macrophage Expression Atlas: a database for expression profiles of macrophages challenged with a variety of pro-inflammatory, anti-inflammatory, benign and pathogen insults. BMC Genomics 6: 178 • Grimes GR, Wen TQ, Mewissen M, Baxter RM, Moodie S, Beattie JS, Ghazal P. 2006. PDQ Wizard: automated prioritization and characterization of gene and protein lists using biomedical literature. Bioinformatics 22: 2055-7 • Moodie SL, Sorokin A, Goryanin I, Ghazal P. 2006. A Graphical Notation to describe the logical interactions of biological pathways. Journal of Integrative Bioinformatics 3 • Laghaee A, Malcolm C, Hallam J, Ghazal P. 2005. Artificial intelligence and robotics in high throughput post-genomics. Drug Discov Today 10: 1253-9 • A. Sorokin, K. Paliy, A. Selkov, O. V. Demin, S. Dronov, P. Ghazal, Goryanin I. 2006. The Pathway Editor: A tool for managing complex biological networks. IBM Journal of Research and Development: Systems Biology 50: 561 • In Press • 7. Taylor C. FD et al. 2007. Promoting Coherent Minimum Reporting Requirements for Biological and Biomedical Investigations: The MIBBI Project. Nature Biotechnology. • Submitted • 8.Amy Buck, Javier Santoyo-Lopez Kevin A Robertson, Reczko M, Ghazal P. 2007. Cytomegalovirus MicroRNA cloning prediction, identification and modulation of host pathway responses. Journal of Virology. (In Review) • 9. Lena Hansson, J.Douglas Armstrong, Ghazal P. 2007. SORGE, a visualization tool for the structural hierarchy of chromosomal, genomic, and gene annotation. BMC Bioinformatics. (In Review) • In Preparation • 10.Andrew D Livingston JJG-R, Ana Angulo, Guillermo López-Campos, Alan J Ross, Marie Craigon, and Peter Ghazal. 2007. Transcriptional profiling and functional annotation of the MCMV genome. To be Confirmed. • 11. Planas J, Robertson KA, Raza S, Freeman TC, Ghazal P, Oliva B. 2007. System level analysis of protein interaction resources and predictions using PIANA. To be confirmed (manuscript in preparation). • 12. Raza S, Robertson KA, Lacaze P, Enright A, Ghazal P, Freeman TC. 2007. An Integrated Map of Pathways Central to the Human Innate-Immune Response; Exploring Issues of Notation and Scalability in Pathway Depiction. To be confirmed. • Planned • 13. Robertson KA, Koutsoudaki E, Raza S, Freeman TC, Ghazal P. 2008. A Computational Framework to support Host-Pathogen Pathway Biology. To be confirmed. Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  2. Final Presentation Strategy The Challenge Pathway Medicine WorkPackage Focus Final Integrated Objective The HCV challenge Results Research and infrastructure support this approach Future challenges and Requirements Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  3. The Challenge Clinical practice, the Systems Alternative: Strategies beyond linear relationships and single parameters Existing Clinical practice: Stepwise tests derived from reductionist research Diagnoses - Experience of the practitioner Isolation of a single factor Evidence-based clinical practice Simultaneous evaluation of multiple factors Homeostasis Recognition of Robustness Single Risk Factor-Disease Analysis Individualised & Minimised treatment Treatment Partitioning Multidimensional & Synergistic Treatments Individualised diagnosis & prognosis Highly Successful: BUT can disregard Component Interactions and their dynamics More effective in chronic and complex diseases? Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  4. A Tractable Strategy: Pathway Medicine Our Pathway Approach: Mapping, understanding, modelling and manipulation of cause-effect relationships Input Output Virus Pharmaceutical Local physiological change Disease Resolution Key Aspects: Pathway Curation Graphical/ computational modelling and simulation of pathways High-throughput Screening and Mechanistic Pathway analyses Data Mining • Benefits • Provides a practical tangible focus • Provides a common language between clinical and technological disciplines Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  5. Antiviral Infectious agent Systemic Therapeutic Host Viral Interaction Networks Host Interaction Networks Hepatitis C infected patient responses to Interferon Therapy 1. Clinically relevant pathways whose behaviour is modulated by interferon. 2. How do pathogens Hepatitis C and Cytomegalovirus engage with these and other pathways to perpetuate their existence within the host? Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  6. WP6.2 Recent Results Update • 120-170 million people infected worldwide (20% cirrhosis and hepatocellular carcinoma) • NO Effective Vaccine • Very High Mutation Rate [1 nucleotide change/ replication] – Drug escape mutants • 6 Major Genotypes: 31% to 33% difference at nucleotide level • Varying sensitivity to ANTIVIRAL AND HOST therapy Response? Weekly injections peg-interferon/ Oral administration of Ribavirin 50% YES 50% NO HCV type 1 1 2 3 Months 70% YES 30% NO HCV type 3 Adverse therapeutic effects: Flu-like symptoms, Reduced Neutrophil count ‘Neutropenia’, Reduced platelet count ‘Thrombocytopenia’ Depression Minimum pharmaceutical cost: ~ £2400 HCV infected patient Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  7. Collaboration with Taylor et al. Positive treatment > 3.5 log10 IU/ml drop or to undetectable on day 28 Non-Response < 1.4 log10 IU/ml decline on day 28 relative to baseline. HCV infected patients 2 7 14 0 1 28 Method: Full genomic expression profiling of HOST PBMC post treatment WP6.2 Recent Results Update How has this been achieved? Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  8. 0.001 0.01 WP6.2 Recent Results Update Positive treatment outcome Non-Responders Day 0 to Day 1 Twice as many genes significantly changed in expression (p<0.01, FC>2) in positive treatment patients (147 vs 76) Common response: 74 genes increased Positive treatment outcome & Non-responders Positive Treatment Outcome ONLY: 26 genes Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  9. db db Pathways Pathways Chi-Squared Analysis of differential Pathway responses in Statistically Significant genes Day 0 and Day 1 Qualatative analysis of differential Pathway responses in expanded protein network 100 0.006 0.005 10 P<0.01 P<0.05 0.004 -Log2 1-tailed p value calculated from Chi-Square statistic Number of curated Pathway Components in expanded list/ Total Components in Pathway Number of genes in statistical List 1 0.003 0.002 0.1 0.001 0.01 0 Positive Treatment Outcome Positive Treatment Outcome Common Response Common Response Interferon TLR Apoptosis HCV Targeted Proteins Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  10. Toll-like Receptors: Family of Molecular Sensors Recognise molecular patterns: TLR3 (dsRNA), TLR7-8 (ssRNA), TLR9 (CpG) Expressed by immune cells Induce Inflammatory Responses • ‘New’ Therapies for HCV • Small Molecule • NS3-4A protease inhibitors – BILN2061*,VX-950* • NS5B RdR polymerase inhibitors – Nucleoside (NM283*) & Non-nucleoside Inhibitors (JTK-109, JTK-003) • Nucleic Acid Antivirals • Anti-sense oligos, ribozymes and siRNA [in vivo delivery & resistance problems] • Novel Immunomodulatory Agents • Synthetic Agonists of TLR 9 (CPG-10101*) and TLR7 (ANA245*, Isatoribine*) ‘Combinations of multiple agents (targetting host and virus) will be required to treat chronic HCV’ Francesco and Migliaccio (2005) Nature 436, 953-960 * Clinical effect, issues with toxicity Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  11. WP6.2 Recent Results Update Research and infrastructure to support the Pathway Medicine Approach Text Mining, Ontologies and Notation development Pathway Curation Host-Pathogen Pathway Database Novel Sequence Analysis Virus-Host Interaction Pathway DB DB Integration, Algorithm development Protein Interaction Network miRNA Prediction pipeline, Algorithm development Cloning Novel Pathway control Laboratory Validation Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  12. Pathway Curation • Focus on clinically relevant immune system pathways • Extensive manual curation: Logic, Technique, Publication, Cell-type • Several Hundred Components involved in thousands of interactions forming pathways • Development of a novel Pathway Notation 1. Moodie SL, Sorokin A, Goryanin I, Ghazal P. 2006. A Graphical Notation to describe the logical interactions of biological pathways. Journal of Integrative Bioinformatics Vol 3. 2. Sorokin, K. Paliy, A. Selkov, O. V. Demin, S. Dronov, P. Ghazal, Goryanin I. 2006. The Pathway Editor: A tool for managing complex biological networks. IBM Journal of Research and Development: Systems Biology 50: 561 3. Sobia Raza, Kevin Robertson, Paul Lacaze, Anton Enright, Peter Ghazal, Tom C. Freeman. 2007. An Integrated Map of Pathways Central to Human Innate-Immune Response; Exploring Issues of Notation and Scalability in Pathway Depiction. Draft Prepared – July Submission Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  13. Pathway Medicine and Drug Discovery Data Standards Systems Biology Graphical Notation: www.sbgn.org Moodie SL, Sorokin A, Goryanin I, Ghazal P. 2006. A Graphical Notation to describe the logical interactions of biological pathways. Journal of Integrative Bioinformatics Vol 3. Minimum Information about a RNA Interference Experiment (MIARIE): www.miare.org Barrios-Rodiles, M. et al. Conceptual design andreporting guidelines for minimum information about an RNAi experiment(MIARE): Towards RNAi data standards. Nature Biotech (In review)(Refereed). Minimum Information Biological and Biomedical Investigations (MIBBI): www.mibbi.org Taylor C et al. (2007) Promoting Coherent Minimum Reporting Requirements for Biological and Biomedical Investigations: The MIBBI Project. Nature Biotechnology, in the press Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  14. System level analysis of protein interaction resources • Objectives: • To analyse ability of PIANA to recreate hand-curated pathways • To establish thresholds for confidence in each data source PIANA exploits • To apply PIANA to prediction of new Pathway components Planas J, Robertson KA, Raza S, Freeman TC, Ghazal P, Oliva B. 2007. System level analysis of protein interaction resources and predictions using PIANA. To be confirmed (manuscript in preparation). Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  15. MicroRNAs – Pathogen subversion of pathway function Prediction Cloning Viral genome sequence Cytomegalovirus Infected cells FORTH sequence prediction pipeline retrained Small RNAs cloned and sequenced predicted precursor sequences Sequence analysis to identify virus-specific mature sequences Refine algorithm Lab Validation New predictions Pathway Focussed Target Prediction Amy Buck, Javier Santoyo-Lopez Kevin A Robertson, Reczko M, Ghazal P. 2007. Cytomegalovirus MicroRNA cloning prediction, identification and modulation of host pathway responses. Journal of Virology. (In Review) Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  16. Pathogen subversion of pathway responses HCMV protein sequence comparison Significant homology between: SLAM Cell-cell recognition Immune Synapse Formation UL7 Ligand Ly9 transfected cells UL7-Fc No Fluorescent Anti-Fc * SLAM UL7 mediates neutrophil binding and could play a role in modulating inflammatory responses Mock pCINeohLy9UL7 pCINeohLy9UL7 + anti-UL7 mab Cos cells transfected with pCINeohLy9UL7 and incubated with neutrophils Pablo EngelMar Alba, KA Robertson, P Ghazal, Ana Angulo Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  17. Host-Pathogen Pathway Database Number of pathogen miRNA Number of Host-Pathogen Protein Interactions* Number of P to P Interactions Number of Hand Curated Pathways* Systems Virology Virus-Host Interactions Number of HPRD Pathways Number of KEGG Pathways Pathway visualisation and exploration (Aug 07) [Elisavet Koutsoudaki] Number of KEGG Interactions 1 10 100 1000 10000 100000 Next: Technical – Workflow, API, AJAX interface Curation: Pharma-mapping, miRNA targets, Disease Association Further Consultation with Nucleic Acid Research/ other Publication: 2008 http://hercules.gti.ed.ac.uk:8080/pathway User: user Password: tester ‘Biolayout Express3D’ Freeman et al. 2007 Final Consortium Meeting, Barcelona, 27th and 28th June 2007

  18. Pathway Medicine and Drug Discovery Future Challenges and Requirements • Pathways • Mapping all network relationships • Boundaries –knowledge vs application • Data Standards: Notation, Ontologies, Exchange PSI-ML, Biopax, SBML, SBGN.org • Genetic Integration • Integration of genetic markers on a pathway-scale • Inference of marker effect on pathway behaviour • Technology and Data • Application of cost-effective techniques – MORE Comprehensive datasets • In vitro & In vivo dynamic pathway behaviour • Clinical Data Integration • Prognostic predictors • Analytical Tools • Modelling and pathwaysimulation • Integration of pathway Omics data • Integration of patient parameters • Pharma-Integration • Global Mapping of drugs to pathways • Exploitation(?) of ‘off target’ systemic effects ‘Use of clinical data and current best evidence coupledwith pathway knowledge to make decisions about the care of individual patients’ Final Consortium Meeting, Barcelona, 27th and 28th June 2007

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