MMD- A Mathematical Modeling Database for Cell Signaling Pathways.

1. 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. Roadmap • Motivation • Need of an Integrative Environment • Knowledge Utilization • Integrative Environment • MMD Core Schema • Results • Current Status of MMD • Discussion and Outlook

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

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

6. Combing Abstract Knowledge Modeling Knowledge Biological Knowledge Modeling Tools Pathway Tools Simulation & Analysis Biological Interpretation

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

8. Organizational Structure of MMD 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. Results Knowledgebase Pathways Reactions Components

9. Database Core Schema Components Reactions Pathways

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

11. Component & Reaction records of MMD

12. Current Status of MMD • We have incorporated biological knowledge from the online protein databases like BIND,DIP and others, into our database. • We implemented and tested the TNFa pathway model based on Cho et al. within our environment. • We extended the TNFa 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. 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. Discussion & Outlook

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