ICATPN 2004, B OLOGNA PN & Systems Biology P ETRI N ET B ASED M ODEL V ALIDATION IN S YSTEMS B IOLOGY Monika Heiner Ina Koch Brandenburg University of Technology Technical University of Applied Sciences Cottbus Berlin Dep. of CS Dep. of Bioinformatics monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , B ASICS PN & Systems Biology chemical reactions -> atomic actions -> Petri net transitions ❑ 2 NAD + + 2 H 2 O -> 2 NADH + 2 H + + O 2 NADH NAD + 2 2 input output 2 H + r1 compounds compounds 2 H 2 O O 2 monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , B ASICS PN & Systems Biology chemical reactions -> atomic actions -> Petri net transitions ❑ 2 NAD + + 2 H 2 O -> 2 NADH + 2 H + + O 2 NADH NAD + 2 2 input output 2 H + r1 compounds compounds 2 H 2 O O 2 chemical compounds -> Petri net places ❑ x y - primary compounds - metabolites - auxiliary compounds, - e. g. electron carrier A r2 B ubiquitous -> fusion nodes enzyme - catalyzing compounds - enzymes monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , B ASICS PN & Systems Biology chemical reactions -> atomic actions -> Petri net transitions ❑ 2 NAD + + 2 H 2 O -> 2 NADH + 2 H + + O 2 NADH NAD + 2 2 input output 2 H + r1 compounds compounds 2 H 2 O O 2 chemical compounds -> Petri net places ❑ x y - primary compounds - metabolites - auxiliary compounds, - e. g. electron carrier A B r2 ubiquitous -> fusion nodes enzyme - catalyzing compounds - enzymes stoichiometric relations -> Petri net arc multiplicities ❑ compounds distribution -> marking ❑ monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 B monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r3: B -> D + E B r3 D C E -> alternative reactions monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 D C F E r6: C + b -> G + c b b r7: D + b -> H + c r6 r7 c c H G -> concurrent reactions monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 r5_rev r5: E + H <-> F D C F E r6: C + b -> G + c r5 b b r7: D + b -> H + c r6 r7 c c r8_rev r8: H <-> G H G r8 -> reversible reactions monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 r5: E + H <-> F r5 D C F E r6: C + b -> G + c b b r7: D + b -> H + c r6 r7 c c r8: H <-> G r8 H G -> reversible reactions - hierarchical nodes monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 r5: E + H <-> F r5 D C F E r6: C + b -> G + c b b r7: D + b -> H + c r6 r7 c c r8: H <-> G r8 H G r9: G + b -> K + c + d b a 29 28 r10: H + 28a + 29c -> 29b c r9 r10 c 2 29 r11 r11: d -> 2a d b K monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 r5: E + H <-> F r5 D C F E r6: C + b -> G + c b b r7: D + b -> H + c r6 r7 c c r8: H <-> G r8 H G r9: G + b -> K + c + d b a 29 28 r10: H + 28a + 29c -> 29b c r9 r10 c 2 29 r11 r11: d -> 2a d b K monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IOLOGICAL S YSTEMS , I NTRO PN & Systems Biology input compound A r1: A -> B r1 r2: B -> C + D r2 r4 a r3: B -> D + E B r4: F -> B + a r3 r5: E + H <-> F r5 D C F E r6: C + b -> G + c b b r7: D + b -> H + c r6 r7 c c r8: H <-> G r8 H G stoichiometric r9: G + b -> K + c + d b a relations 29 28 r10: H + 28a + 29c -> 29b c r9 r10 c 2 29 r11 r11: d -> 2a d b K fusion nodes - auxiliary compounds output compound monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IONETWORKS PN & Systems Biology networks of chemical reactions ❑ biologically interpreted Petri net ❑ -> partial order sequences of chemical reactions - transforming input into output compounds - respecting the given stoichiometric relations monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IONETWORKS PN & Systems Biology networks of chemical reactions ❑ biologically interpreted Petri net ❑ -> partial order sequences of chemical reactions - transforming input into output compounds - respecting the given stoichiometric relations typical (structural) properties ❑ INA ORD HOM NBM PUR CSV SCF CON SC Ft0 tF0 Fp0 pF0 MG SM FC EFC ES N N N Y N N Y N N N Y Y N N N N N DTP CPI CTI B SB REV DSt BSt DTr DCF L LV L&S N N N Y Y ? ? ? ? ? N ? N observation ❑ -> tend to grow fast monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IONETWORKS PN & Systems Biology networks of chemical reactions ❑ biologically interpreted Petri net ❑ -> partial order sequences of chemical reactions - transforming input into output compounds - respecting the given stoichiometric relations typical (structural) properties ❑ INA ORD HOM NBM PUR CSV SCF CON SC Ft0 tF0 Fp0 pF0 MG SM FC EFC ES N N N Y N N Y N N N Y Y N N N N N DTP CPI CTI B SB REV DSt BSt DTr DCF L LV L&S N N N Y Y ? ? ? ? ? N ? N observation ❑ -> tend to grow fast monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
B IONETWORKS , SOME P ROBLEMS PN & Systems Biology network structure ❑ -> PROBLEM 1 -> dense, apparently unstructured -> hard to read knowledge ❑ -> PROBLEM 2 -> uncertain -> growing, changing -> distributed over independent data bases, papers, journals, . . . various, mostly ambiguous representations ❑ -> PROBLEM 3 -> verbose descriptions -> diverse graphical representations -> contradictory and / or fuzzy statements -> some examples monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
N ETWORK R EPRESENTATIONS , E X 1 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 -> CASE STUDY 1 Apoptosis monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
N ETWORK R EPRESENTATIONS , E X 1 + E X 2 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 -> CASE STUDY 1 Apoptosis monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
N ETWORK R EPRESENTATIONS , E X 1 + E X 2 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 -> CASE STUDY 1 Apoptosis monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
N ETWORK R EPRESENTATIONS , E X 3 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 -> CASE STUDY 1 monika.heiner@informatik.tu-cottbus.de, ina.koch@tfh-berlin.de June 2004
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