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

I M S BRoadmap

• Motivation

• Need of an Integrative Environment

• Knowledge Utilization

• Integrative Environment

• MMD Core Schema

• Results

• Current Status of MMD

• Discussion and Outlook

I M S BMotivation and GoalMotivation

• 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.

I M S BNeed of an Integrative EnvironmentHypothesizedmechanistic

diagram

Experimentaldesign

Mathematicalmodeling

Mathematical analysis

Predictions

Experimentalmethods

Time coursemeasured data

Match ?

No

SimulationTranslation

I M S BKnowledge Utilization

Conceptual Models

Biocarta: EGF MAPK Kaskade

Mathematical Model

Biological Databases

Schoeberl B et al. Nat Biotechnol. 2002 Apr;20(4):370-5.

I M S B

Biological Knowledge Modeling Knowledge

Modeling Tools

Simulation &Analysis

Pathway Tools

Biological Interpretation

Combing Abstract Knowledge

I M S B

KEGG

DIP

GO

IntegratedWorkspace

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,DIPBiological

Dataset

SimulationDataset

Modeling Dataset

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

I M S BDatabase Core Schema

Components

Reactions

Pathways

I M S B A Model stored in MMDBouwmeester T, etal. Nat Cell Biol. 2004 Feb;6(2):97-105

TNF pathway model.Cho KH, etal. Simulation. 2003 Dec;79(12):726-39

I M S BComponent & Reaction records of MMD

Component_ID

Name Component_Description

Disease

Formula

Source

Created

1472 TNFR1 Tumor 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

Biological

28.01.20

04 14:44:05

Reaction_ID Reaction_Name Reaction_Description Disease Reaction_Formu

la Created Datasource

40105 TNFalpha/TNFR1 association and dissociation

-(k1)*(m1)*(m2) +(k2)*(m3) +(k24)*(m24) +(k13)*(m12)

05.07.2004 11:42:46

IMSB

I M S BCurrent 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 TNFpathway model based on Cho et al. within our environment.

3. We extended the TNFpathway 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).

I M S BDiscussion & 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.

I M S BTeam

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.