1. I M S B MMD- A Mathematical Modeling Database for Cell Signaling Pathways. V. Mahesh*, M. Breit, G. Enzenberg, B. Pfeifer, R. Modre-Osprian, B. Tilg Institute for Biomedical Signal Processing and Imaging, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria. mahesh.visvanathan@umit.at imsb.umit.at DBiBD 2005 National e-Science Centre, Edinburgh, Scotland, UK

2. I M S B Roadmap Motivation Need of an Integrative Environment Knowledge Utilization Integrative Environment MMD Core Schema Results Current Status of MMD Discussion and Outlook

3. I M S B Motivation and Goal Motivation Improving the level of understanding cell signaling pathways will have a number of potential and practical applications for medications and drug design. For example TNFα mediated NF-κB signaling pathway takes part in: –Cancer, Diabetes, Morbus Crohn –Protein-Protein Interaction-Networks. Goal Building up of a knowledgebase. That stores biological information. That stores modeling information (including mathematical models) concerning pathways.

4. I M S B Need of an Integrative Environment Hypothesized mechanistic diagram Experimental design Mathematical modeling Mathematical analysis Predictions Experimental methods Time course measured data Match ? No Simulation Translation

5. I M S B Knowledge Utilization Conceptual Models Biocarta: EGF MAPK Kaskade Mathematical ModelBiological Databases Schoeberl B et al. Nat Biotechnol. 2002 Apr;20(4):370-5.

6. I M S B Biological Knowledge Modeling Knowledge Modeling Tools Simulation & Analysis Pathway Tools Biological Interpretation Combing Abstract Knowledge

7. I M S B KEGG DIP GO Integrated Workspace Mathematical Modeling Database Designing Environment Data exchange between PathBlazer and MMD BIND CZDB Modeling data handling Simulation Environment Integrative Environment MS-SQL Server2000 Data exchange between Matlab and MMD BIND,DIP Biological Dataset Simulation Dataset Modeling Dataset

8. I M S B Knowledgebase (KB): Information about pathways, interactions and their association to components that includes modeling dataset. Pathways: A group of interacting components. Reactions: A group of components that undergo a transformation. Components: It can be a protein, DNA/RNA, sub molecule, etc that is involved in a reaction. Organizational Structure of MMD Results Pathways Reactions Components Knowledgebase

9. I M S B Database Core Schema Components Reactions Pathways

10. I M S B A Model stored in MMD Bouwmeester T, etal. Nat Cell Biol. 2004 Feb;6(2):97-105 TNF pathway model. Cho KH, etal. Simulation. 2003 Dec;79(12):726-39

11. I M S B Component & Reaction records of MMD Com pone nt_I D NameComponent_Description DiseaseDisease FormulaFormula SourceSource Cre ated 147 2 TNFR1Tumor necrosis factor receptor superfamily, member 1A; tumor necrosis factor-alpha receptor; tumor necrosis factor binding protein 1. A member of the TNF-receptor superfamily. One of the major receptors for the tumor necrosis factor-alpha. Germline mutations of the extracellular domains of this receptor were found to be associated with the autosomal dominant periodic fever syndrome. Note that the GI refers to an incomplete description of the molecule, [mat_peptide:22-455]. OMIM:191190 B io lo gi c al 28.0 1.20 04 14:4 4:05 Reaction_ID Reaction_Name Reaction_Des cription Disease Reaction_Formu la Created Dataso urce 40105TNFalpha/TNFR1 association and dissociation -(k1)*(m1)*(m2) +(k2)*(m3) +(k24)*(m24) +(k13)*(m12) 05.07.2004 11:42:46 IMSB

12. Current Status of MMD 1.We have incorporated biological knowledge from the online protein databases like BIND,DIP and others, into our database. 2.We implemented and tested the TNF pathway model based on Cho et al. within our environment. 3.We extended the TNF pathway model of Cho using the integrative environment. 4.We implemented data handling tools between different parts of the integrative environment, e.g., pathway-XML file handling tool in Matlab to extract modeling information (set of ODEs).

13. I M S B Discussion & Outlook Expanding the Database Schema - Experimental and Clinical data. - Protein complex building. - Validation of implemented pathway models. Further Work - Extending the database schema for including simulation results. - Incorporate a flexible data exchange format using XML that supports us to exchange the data e.g., using Biopax. - Incorporating BIOUML or Cytoscape tool into our environment for a more global visualization.

14. I M S B Team Integrativer Environment, Database Computational Systems Biology Biological and Clinical Questions Modeling and Simulation of Signaling Pathways. Mahesh Visvanathan, M.Sc. Breit Marc, M.Sc. Enzenberg Gernot, Dr. Bernhard Pfeifer, Dip.-Ing. Modre-Osprian Robert, Dr. Tilg Bernhard, Prof., Dr.