HU B ERLIN , A PRIL 2005 PN & Systems Biology M ODELLING OF B IOCHEMICAL N ETWORKS WITH T IME P ETRI N ETS Monika Heiner Brandenburg University of Technology Cottbus, Department of CS monika.heiner@informatik.tu-cottbus.de April 2005
M ODEL - BASED S YSTEM A NALYSIS PN & Systems Biology system Problem system properties model Petrinetz model properties monika.heiner@informatik.tu-cottbus.de April 2005
M ODEL - BASED S YSTEM A NALYSIS PN & Systems Biology system Problem system properties verification technical requirement CONSTRUCTION system specification model Petrinetz model properties monika.heiner@informatik.tu-cottbus.de April 2005
M ODEL - BASED S YSTEM A NALYSIS PN & Systems Biology system Problem system properties known validation properties biological UNDERSTANDING system unknown behaviour properties prediction model Petrinetz model properties monika.heiner@informatik.tu-cottbus.de April 2005
PN & Systems Biology W HAT KIND OF MODEL SHOULD BE USED ? monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 1 PN & Systems Biology KEGG Caspase cascade APOPTOSIS CASP4 CASP11 CASP1 FAP-1 Daxx CSP10 CASP6 FasL Fas FADD CASP8 CASP3 DFF45 CASP7 TNF α TNFR1 TRADD RIP CASP2 RAIDD Mitochondria rupture DFF40 Cytc CASP9 TRF2 TNF β TNFR2 TRF1 NF-kB Nucleus TRF3 Apaf-1 DNA fragmentation CD40L TRF6 CD40 Bcl-w Glucocortocoid Mcl-1 A-1 GR I-kB Mtd NGF p75LNTR Bcl-xL Bcl-2a trkA Bax Hrk Bad monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 1 PN & Systems Biology KEGG Caspase cascade APOPTOSIS CASP4 CASP11 CASP1 FAP-1 Daxx CSP10 CASP6 FasL Fas FADD CASP8 CASP3 DFF45 CASP7 TNF α TNFR1 TRADD RIP CASP2 RAIDD Mitochondria rupture DFF40 Cytc CASP9 TRF2 TNF β TNFR2 TRF1 NF-kB Nucleus TRF3 Apaf-1 DNA fragmentation CD40L TRF6 CD40 Bcl-w Glucocortocoid -> INHIBITOR Mcl-1 A-1 GR I-kB ARCS Mtd NGF p75LNTR Bcl-xL Bcl-2a trkA Bax Hrk Bad monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 1 PN & Systems Biology KEGG Caspase cascade APOPTOSIS CASP4 CASP11 CASP1 FAP-1 Daxx CSP10 CASP6 FasL Fas FADD CASP8 CASP3 DFF45 CASP7 TNF α TNFR1 TRADD RIP CASP2 RAIDD Mitochondria rupture DFF40 Cytc CASP9 TRF2 TNF β TNFR2 TRF1 NF-kB Nucleus TRF3 Apaf-1 DNA fragmentation CD40L TRF6 CD40 Bcl-w Glucocortocoid -> INHIBITOR Mcl-1 A-1 GR I-kB ARCS Mtd NGF p75LNTR Bcl-xL Bcl-2a -> ERROR trkA Bax Hrk Bad monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 1 PN & Systems Biology Caspase cascade APOPTOSIS -> INTERPRETATION ? CASP4 CASP11 CASP1 FAP-1 Daxx CSP10 CASP6 FasL Fas FADD CASP8 CASP3 DFF45 CASP7 TNF α TNFR1 TRADD RIP CASP2 RAIDD Mitochondria rupture DFF40 Cytc CASP9 TRF2 TNF β TNFR2 TRF1 NF-kB Nucleus TRF3 Apaf-1 DNA fragmentation CD40L TRF6 CD40 Bcl-w Glucocortocoid -> INHIBITOR Mcl-1 A-1 GR I-kB ARCS Mtd NGF p75LNTR Bcl-xL Bcl-2a -> ERROR trkA Bax Hrk Bad monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 2 PN & Systems Biology 4 Ru5P Xu5P 5 S7P E4P 6 7 8 2 NADPH 2 GSSG GAP F6P R5P 3 2 1 2 NADP + 4 GSH 9 10 11 12 Gluc G6P F6P FBP GAP 13 14 ATP ADP ATP ADP NAD + DHAP + Pi 15 NAD + NADH NADH ATP ADP ATP ADP 20 19 18 17 16 Lac Pyr PEP 2PG 3PG 1,3-BPG monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 2 PN & Systems Biology 4 Ru5P Xu5P 5 S7P E4P 6 7 8 2 NADPH 2 GSSG GAP F6P R5P 3 2 1 2 NADP + 4 GSH ?? ?? 9 10 11 12 Gluc G6P F6P FBP GAP 13 14 ATP ADP ATP ADP NAD + DHAP + Pi 15 NAD + NADH NADH ATP ADP ATP ADP 20 19 18 17 16 Lac Pyr PEP 2PG 3PG 1,3-BPG monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 2 PN & Systems Biology 4 Ru5P Xu5P 5 S7P E4P 6 7 8 2 NADPH 2 GSSG GAP F6P R5P 3 2 1 2 NADP + 4 GSH -> INTERPRETATION ? 9 10 11 12 Gluc G6P F6P FBP GAP 13 14 ATP ADP ATP ADP NAD + DHAP + Pi 15 NAD + NADH NADH ATP ADP ATP ADP 20 19 18 17 16 Lac Pyr PEP 2PG 3PG 1,3-BPG monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 3 PN & Systems Biology TNF TNFR1 Fas-L FAN RIP NSMase Fas MADD FADD DAXX Procaspase-8 TRAF2 Ask1 FADD Procaspase-8 FLIP CrmA MAPK Pathway JNK Caspase-8 Effector Caspases Bcl-X Caspases-3,-6,-7 Apoptosis monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 3 + E X 4 PN & Systems Biology TNF Death ligand Death receptor TNFR1 Apoptotic Stimuli FADD Apaf-1 Fas-L Bax, Bad, Bim FAN RIP Bcl-2, Bcl-XL Procaspase-8 NSMase Fas Cytochrome c dATP/ATP MADD FADD DAXX Caspase-8 Procaspase-8 Bid TRAF2 Procaspase-3,-6,-7 Mitochondrion Ask1 FADD Procaspase-9 Active Procaspase-8 FLIP Caspase-3,-6,-7 Procaspase-3,-6,-7 Active Caspase-9 DFF Cleaved DFF45 CrmA MAPK Pathway Oligomer of DFF40 JNK nucleus Caspase-8 Chromatin Condensation and Fragmentation Effector Caspases Bcl-X Caspases-3,-6,-7 Apoptosis monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 3 + E X 4 PN & Systems Biology TNF Death ligand Death receptor TNFR1 Apoptotic Stimuli FADD Apaf-1 Fas-L Bax, Bad, Bim FAN RIP Bcl-2, Bcl-XL Procaspase-8 NSMase Fas Cytochrome c dATP/ATP MADD FADD DAXX Caspase-8 Procaspase-8 Bid TRAF2 Procaspase-3,-6,-7 Mitochondrion Ask1 FADD Procaspase-9 Active Procaspase-8 FLIP Caspase-3,-6,-7 Procaspase-3,-6,-7 Active Caspase-9 DFF Cleaved DFF45 CrmA MAPK Pathway -> INHIBITOR Oligomer of DFF40 JNK ARCS nucleus Caspase-8 Chromatin Condensation and Fragmentation Effector Caspases Bcl-X Caspases-3,-6,-7 Apoptosis monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 3 + E X 4 PN & Systems Biology -> FORMAL SEMANTICS ? TNF Death ligand Death receptor TNFR1 Apoptotic Stimuli FADD Apaf-1 Fas-L Bax, Bad, Bim FAN RIP Bcl-2, Bcl-XL Procaspase-8 NSMase Fas Cytochrome c dATP/ATP MADD FADD DAXX Caspase-8 Procaspase-8 Bid TRAF2 Procaspase-3,-6,-7 Mitochondrion Ask1 FADD Procaspase-9 Active Procaspase-8 FLIP Caspase-3,-6,-7 Procaspase-3,-6,-7 Active Caspase-9 DFF Cleaved DFF45 CrmA MAPK Pathway Oligomer of DFF40 JNK nucleus Caspase-8 Chromatin Condensation and Fragmentation Effector Caspases Bcl-X Caspases-3,-6,-7 Apoptosis monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 5 PN & Systems Biology monika.heiner@informatik.tu-cottbus.de April 2005
N ETWORK R EPRESENTATIONS , E X 5 PN & Systems Biology -> READABILITY ? monika.heiner@informatik.tu-cottbus.de April 2005
B IONETWORKS , SOME P ROBLEMS PN & Systems Biology various, mostly ambiguous representations ❑ -> PROBLEM 1 -> verbose descriptions -> diverse graphical representations -> contradictory and / or fuzzy statements knowledge ❑ -> PROBLEM 2 -> uncertain -> growing, changing -> distributed over independent data bases, papers, journals, . . . network structures ❑ -> PROBLEM 3 -> tend to grow fast -> dense, apparently unstructured -> hard to read - - >> models are full of ASSUMPTIONS << - - monika.heiner@informatik.tu-cottbus.de April 2005
F RAMEWORK PN & Systems Biology bionetworks knowledge quantitative modelling understanding quantitative model validation analysis /simulation models ODEs quantitative behaviour prediction monika.heiner@informatik.tu-cottbus.de April 2005
F RAMEWORK PN & Systems Biology bionetworks knowledge qualitative modelling understanding Petri net theory (invariants) animation / qualitative model validation analysis models model qualitative checking behaviour prediction quantitative quantitative parameters modelling understanding quantitative model validation analysis /simulation models ODEs quantitative behaviour prediction monika.heiner@informatik.tu-cottbus.de April 2005
F RAMEWORK PN & Systems Biology bionetworks knowledge qualitative modelling understanding Petri net theory (invariants) animation / qualitative model validation analysis models model qualitative checking behaviour prediction quantitative quantitative parameters modelling understanding quantitative model validation analysis /simulation models ODEs quantitative behaviour prediction monika.heiner@informatik.tu-cottbus.de April 2005
F RAMEWORK PN & Systems Biology bionetworks knowledge qualitative modelling understanding Petri net theory (invariants) animation / qualitative model validation analysis models model qualitative checking behaviour prediction quantitative quantitative parameters modelling understanding R G S L I animation / quantitative model validation L P analysis /simulation models ODEs quantitative behaviour prediction monika.heiner@informatik.tu-cottbus.de April 2005
PN & Systems Biology P ETRI NETS - AN INFORMAL CRASH COURSE monika.heiner@informatik.tu-cottbus.de April 2005
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