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WP6.2 Genomics and microbiology

WP6.2 Genomics and microbiology. Overall Objective: To demonstrate how the integration of pathway biology And host/ pathogen genomics can contribute to clinical diagnosis and treatment of infected patients. 1 st Annual Technical Review, Brussels, 16 th March 2005. UEDIN. LEIC. INFORMA.

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WP6.2 Genomics and microbiology

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  1. WP6.2 Genomics and microbiology Overall Objective: To demonstrate how the integration of pathway biology And host/ pathogen genomics can contribute to clinical diagnosis and treatment of infected patients 1st Annual Technical Review, Brussels, 16th March 2005

  2. UEDIN LEIC INFORMA IMIM FORTH WP6.2 Genomics and microbiology Work Package approach To forge a collaboration between partners through the integrated study of host/ pathogen interactions WP6.2 Partners Project Lead: P Ghazal K Robertson M Mewissen G Sing A Livingston T Brooks M Alba B Oliva Joan Planas Roberto Ricci Maurizio Zazzi M Reczko 1st Annual Technical Review, Brussels, 16th March 2005

  3. WP6.2 Genomics and microbiology Host pathway: Interferon Signalling > A family of related proteins > Bind to specific receptors Activation of Interferon signalling pathways results in a defined gene expression and: Increased antigen presentation Inhibition of cellular proliferation Development of an inflammatory response An anti-infective state 1st Annual Technical Review, Brussels, 16th March 2005

  4. WP6.2 Genomics and microbiology Interferon is a key Inflammatory mediator with a number of notable therapeutic applications 1st Annual Technical Review, Brussels, 16th March 2005

  5. WP6.2 Genomics and microbiology Medical Informatics Bioinformatics Viral Immuno- modulatory Interactions Clinical Host/ Viral Interactions Outcomes: Secretome 1. Further insight into the virus-host interaction 2. Identification of biomarkers for validation and potential therapeutic exploitation 3. Methods for storage, manipulationand exchange of phenotype data Protein Interaction Network microRNA Phenotype DB Microarray/ Proteomic Profiling 1st Annual Technical Review, Brussels, 16th March 2005

  6. WP6.2 Genomics and microbiology Viral Immunomodulatory Interactions (IMIM/ UEDIN) Objectives: To characterise protein-protein interactions: 1. Within host interferon signalling pathway 2. Between virus and host proteins Objective 1. Application of PIANA to identification of virus/ host protein interaction PIANA Yeast interactions experimentally defined by yeast 2 hybrid approach Gene COG code x 1 2 3 x y z x 7 predicted CMV-Human protein interactions e.g. KPNA4 x x 2. Interacting pairs in yeast defined which have at least 1 COG code in common with CMV proteins 1. COG codes assigned to Human CMV proteins 3. Orthologous human partner identified 1st Annual Technical Review, Brussels, 16th March 2005

  7. WP6.2 Genomics and microbiology Viral Immunomodulatory Interactions (IMIM/ UEDIN) KPNA4 (importin alpha 3) Functions in import of IRF3 into nucleus from cytoplasm Kumar KP, McBride KM, Weaver BK, Dingwall C, Reich NC.Regulated nuclear-cytoplasmic localization of interferon regulatory factor 3, a subunit of double-stranded RNA-activated factor 1 Mol Cell Biol 2000 Jun 1;20(11):4159-68. 1st Annual Technical Review, Brussels, 16th March 2005

  8. WP6.2 Genomics and microbiology Sub-cellular Logic Interaction map of interferon signalling pathway submodule CMV dUTPase 1st Annual Technical Review, Brussels, 16th March 2005

  9. WP6.2 Genomics and microbiology How can a bioinformatics analysis of host-pathogen pathway interactions facilitate clinical patient management? Anti-Retroviral Cohort Analysis (ARCA) db > Stores clinical and HIV genome data (>3000 patients) from multicentric observational cohort in Italy > Enables exploitation of HIV genotype data to advanced HAART therapy 230 patients identified Multiple samples available Full treatment history HIV genotypic data available Key Question: Can host bioinformatics pathway information be incorporated into medical informatics DB and predictive models? 100 patients Host Pathogen HLA typing IFN genotyping CMV status Hepatitis G status Curation into ARCA DB Therapeutic modelling Clinical Host/ Pathogen Interaction data IFN Knowledgebase 1st Annual Technical Review, Brussels, 16th March 2005

  10. WP6.2 Genomics and microbiology Milestones and Objectives Year 2 Year 3 Year 1 Project definition (UEDIN, IMIM, LEIC, FORTH, INFORMA) Data acquisition and curation Protein to protein interactions defined miRNA stem loop identification Novel genes experimentally identified Genotyping/ infection status Data analysis & Integration Pathway Biomarker Validation POC study on benefit from integrating clinical and bio- informatics Biomarker definition Project Plan Preparation of Publications 1st Annual Technical Review, Brussels, 16th March 2005

  11. WP6.2 Genomics and microbiology Efforts towards characterisation of IFN signalling pathway and identification of potential/ novel genes/ proteins of (clinical) interest 1st Annual Technical Review, Brussels, 16th March 2005

  12. WP6.2 Genomics and microbiology Objective 1: Identification of a core set of interferon Gamma-related genes/ proteins around which initial studies of WP6.2 will focus UEDIN ‘novel’ Genes (300 – 400) 263 Core interferon gamma response genes identified Human/Mouse, Variety of cell types Literature Review Ingenuity Pathway Assist Core Literature ‘novel’ genes 1st Annual Technical Review, Brussels, 16th March 2005

  13. WP6.2 Genomics and microbiology Literature Review (PubMed) Several Hundred gene/ gene products Subjective/ Objective Reduction and assortment Antigen Presentation Jak/ STAT IRF(s) Apoptosis Ingenuity Pathway Assist Further novel signalling interactions identified Core genes for analysis Annotation (inc hand-curated protein-protein interaction data) 1st Annual Technical Review, Brussels, 16th March 2005

  14. WP6.2 Genomics and microbiology Actual number of genes involved in interferon response likely to be >1000 A system is required for storage and application of data ‘Interferon Knowledgebase’ 1st Annual Technical Review, Brussels, 16th March 2005

  15. WP6.2 Genomics and microbiology • Year 1 aims for knowledgebase development: • 1) Web accessible repository of interferon signalling-related information • 2) Incorporate data generated in course of InfoBiomed project • Year 2 aims for knowledgebase environment • Incorporate further signalling pathway information (type 1 interferon, TLR • TNF-alpha) selected via objective criteria. • 2) To integrate database with GPX database and allow • rapid focussed analyses of microarray/ proteomic data • 3) Output signalling pathway information from database in XML • (SBML-like) allowing modelling/ simulation 1st Annual Technical Review, Brussels, 16th March 2005

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