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BIOMD0000000227 - Radulescu2008_NFkB_hierarchy_M_39_65_90

 

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Reference Publication
Publication ID: 18854041
Radulescu O, Gorban AN, Zinovyev A, Lilienbaum A.
Robust simplifications of multiscale biochemical networks.
BMC Syst Biol 2008; 2: 86
IRMAR (CNRS UMR 6025), UniversitĂ© de Rennes 1, Rennes, France. ovidiu.radulescu@univ-rennes1.fr  [more]
Model
Original Model: BIOMD0000000227.origin
Submitter: Andrei Zinovyev
Submission ID: MODEL7743656488
Submission Date: 27 Feb 2009 16:34:41 UTC
Last Modification Date: 03 Jun 2014 13:57:34 UTC
Creation Date: 19 May 2008 14:17:56 UTC
Encoders:  Vijayalakshmi Chelliah
   Ovidiu Radulescu
set #1
bqmodel:isDerivedFrom BioModels Database Hoffmann2002_WT_IkBNFkB_Signaling
BioModels Database Hoffmann2002_KnockOut_IkBNFkB_Signaling
PubMed 15094015
set #2
bqbiol:isVersionOf Gene Ontology I-kappaB kinase/NF-kappaB signaling
set #3
bqbiol:isPartOf KEGG Pathway T cell receptor signaling pathway - Mus musculus (mouse)
set #4
bqbiol:hasTaxon Taxonomy Mus musculus
Notes

NFkB model M(39,65,90) - most complex model

This is a model of NFkB pathway functioning from hierarchy of models of decreasing complexity, created to demonstrate application of model reduction methods proposed in

Robust simplifications of multiscale biochemical networks.
Radulescu O, Gorban A., Zinovyev A., Lilienbaum. A. BMC Syst Biol2008:2:86 18854041,
Abstract:
BACKGROUND: Cellular processes such as metabolism, decision making in development and differentiation, signalling, etc., can be modeled as large networks of biochemical reactions. In order to understand the functioning of these systems, there is a strong need for general model reduction techniques allowing to simplify models without loosing their main properties. In systems biology we also need to compare models or to couple them as parts of larger models. In these situations reduction to a common level of complexity is needed. RESULTS: We propose a systematic treatment of model reduction of multiscale biochemical networks. First, we consider linear kinetic models, which appear as "pseudo-monomolecular" subsystems of multiscale nonlinear reaction networks. For such linear models, we propose a reduction algorithm which is based on a generalized theory of the limiting step that we have developed in 1. Second, for non-linear systems we develop an algorithm based on dominant solutions of quasi-stationarity equations. For oscillating systems, quasi-stationarity and averaging are combined to eliminate time scales much faster and much slower than the period of the oscillations. In all cases, we obtain robust simplifications and also identify the critical parameters of the model. The methods are demonstrated for simple examples and for a more complex model of NF-kappaB pathway. CONCLUSION: Our approach allows critical parameter identification and produces hierarchies of models. Hierarchical modeling is important in "middle-out" approaches when there is need to zoom in and out several levels of complexity. Critical parameter identification is an important issue in systems biology withpotential applications to biological control and therapeutics. Our approach also deals naturally with the presence of multiple time scales, which is a general property of systems biology models.

The models are provided in CellDesigner v3.5 format. The name of the model M(x,y,z) should be deciphered as following:

x - number of species y - number of reactions z - number of parameters

Simulation protocol: The model can be simulated in CellDesigner directly, or in any simulator supporting events. The simulation period should be set up in 40 hours (t=144000 sec). The 'signal' event applies signal to the pathway at the moment t=20 hours=72000 sec. This model reproduces Figure 7c (M(39,65,90)) of the publication.

For additional information please contact Andrei.Zinovyev at curie.fr

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.
For more information see the terms of use.
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 18854041 Submission Date: 27 Feb 2009 16:34:41 UTC Last Modification Date: 03 Jun 2014 13:57:34 UTC Creation Date: 19 May 2008 14:17:56 UTC
Mathematical expressions
Reactions
re1 re8 re14 re15
re19 re20 re21 re22
re23 re24 re25 re26
re27 re28 re29 re30
re31 re32 re33 re34
re35 re36 re37 re38
re39 re40 re41 re42
re43 re44 re45 re46
re47 re48 re49 re52
re53 re56 re57 re58
re59 re60 re61 re62
re63 re64 re65 re66
re67 re68 re69 re70
re71 re72 re74 re75
re76      
Events
signal      
Physical entities
Compartments Species
default sa4_degraded p105 sa438_degraded
sa3_degraded mRNAp105 p50
mRNAp65 sa8_degraded p65
sa9_degraded sa13_degraded IkB_alpha
sa12_degraded mRNAA20 A20
sa444_degraded IKKi sa19_degraded
IKKa IKKn sa20_degraded
sa96_degraded sa97_degraded csa21_degraded
csa18_degraded mRNAIKB_alpha NFkB:IkB_alpha
NFkB:IKKa:Ikb_alpha NFkB IKKa:IKB_alpha
     
nucleus FTAx FTAy FTAz
IkB_alpha csa17_degraded A20
IKK csa9_degraded InactivePRaseonp65
ActivePRaseonp65 InactivePRaseonp105 ActivePRaseonp105
ActivePRaseonIkB_alpha NFkB:IkB_alpha Promp65:RNAP2
Promp65:RNAP2:FTAy NFkB Promp105:RNAP1:p50p65
Promp105:RNAP1:p50p65:IkBa Promp105:RNAP Promp105:RNAP:FTAX
Promp105:RNAP1:FTAx:p50p65 Promp105:RNAP1:FTAx:p50p65:IkBa PromIkBa:RNAP3
PromIkBa:RNAP3:FTAz InactivePRaseonIkB_alpha PromIkBa:RNAP3:p50p65
PromIkBa:RNAP3:p50p65:IkBa IkBa:RNAP3:FTAz:p50p65 PromIkBa:RNAP3:FTAz:p50p65:IkB_alpha
Global parameters
k1 k2 k3 k4
k5 k6 k7 k8
k9 k10 k11 k12
kf13 kr13 kf14 kr14
kf15 kr15 k16 k17
k18 k20 k19 k21
k22 kf23 kr23 k25
k27 kf28 kr28 kf32
kr32 k42 k43 k33
k34 k69 k70 k49
k50 k61 k62 k35
k36 k37 k38 k39
k40 kf41 kr41 k44
k45 k46 k47 kf48
kr48 k51 kf52 kr52
k53 k54 kf55 kr55
kf56 kr56 kf57 kr57
kf58 kr58 kf59 kr59
kf60 kr60 kf63 kr63
kf64 kr64 kf65 kr65
kf66 kr66 kf67 kr67
kf68 kr68 k71 k72
Reactions (57)
 
 re1 [FTAx] + [Promp105:RNAP] → [Promp105:RNAP:FTAX];  
 
 re8 [Promp105:RNAP:FTAX] + [NFkB] → [Promp105:RNAP1:FTAx:p50p65];  
 
 re14 [NFkB] + [PromIkBa:RNAP3:FTAz] → [IkBa:RNAP3:FTAz:p50p65];  
 
 re15 [IkB_alpha] + [PromIkBa:RNAP3:p50p65] → [PromIkBa:RNAP3:p50p65:IkBa];  
 
 re19 [NFkB] + [Promp105:RNAP] → [Promp105:RNAP1:p50p65];  
 
 re20 [Promp105:RNAP1:p50p65] + [IkB_alpha] → [Promp105:RNAP1:p50p65:IkBa];  
 
 re21 [NFkB] + [PromIkBa:RNAP3] → [PromIkBa:RNAP3:p50p65];  
 
 re22 [Promp105:RNAP1:FTAx:p50p65] + [IkB_alpha] → [Promp105:RNAP1:FTAx:p50p65:IkBa];  
 
 re23 [IkB_alpha] + [IkBa:RNAP3:FTAz:p50p65] → [PromIkBa:RNAP3:FTAz:p50p65:IkB_alpha];  
 
 re24 [FTAz] + [PromIkBa:RNAP3] → [PromIkBa:RNAP3:FTAz];  
 
 re25 [Promp105:RNAP1:p50p65:IkBa] → [Promp105:RNAP] + [NFkB:IkB_alpha];  
 
 re26 [Promp105:RNAP1:FTAx:p50p65:IkBa] → [Promp105:RNAP:FTAX] + [NFkB:IkB_alpha];  
 
 re27 [PromIkBa:RNAP3:FTAz:p50p65:IkB_alpha] → [PromIkBa:RNAP3:FTAz] + [NFkB:IkB_alpha];  
 
 re28 [PromIkBa:RNAP3:p50p65:IkBa] → [PromIkBa:RNAP3] + [NFkB:IkB_alpha];  
 
 re29 [Promp65:RNAP2] + [FTAy] → [Promp65:RNAP2:FTAy];  
 
 re30 [InactivePRaseonp65] → [ActivePRaseonp65];   {Promp65:RNAP2} , {Promp65:RNAP2:FTAy}
 
 re31 [InactivePRaseonp105] → [ActivePRaseonp105];   {Promp105:RNAP1:FTAx:p50p65} , {Promp105:RNAP:FTAX} , {Promp105:RNAP} , {Promp105:RNAP1:p50p65}
 
 re32 [InactivePRaseonIkB_alpha] → [ActivePRaseonIkB_alpha];   {IkBa:RNAP3:FTAz:p50p65} , {PromIkBa:RNAP3:p50p65} , {PromIkBa:RNAP3} , {PromIkBa:RNAP3:FTAz}
 
 re33 [NFkB] → [csa17_degraded];  
 
 re34 [ActivePRaseonp105] → [mRNAp105];  
 
 re35 [p105] → [sa4_degraded];  
 
 re36 [mRNAp105] → [sa3_degraded];  
 
 re37 [mRNAp105] → [p105] + [mRNAp105];  
 
 re38 [p105] → [p50];  
 
 re39 [p50] → [sa438_degraded];  
 
 re40 [ActivePRaseonp65] → [mRNAp65];  
 
 re41 [mRNAp65] → [sa8_degraded];  
 
 re42 [p65] → [sa9_degraded];  
 
 re43 [mRNAp65] → [p65] + [mRNAp65];  
 
 re44 [ActivePRaseonIkB_alpha] → [mRNAIKB_alpha];  
 
 re45 [mRNAIKB_alpha] → [sa12_degraded];  
 
 re46 [IkB_alpha] → [sa13_degraded];  
 
 re47 [mRNAIKB_alpha] → [IkB_alpha] + [mRNAIKB_alpha];  
 
 re48 [A20] → [mRNAA20];   {NFkB}
 
 re49 [IKKn] → [IKKa];  
 
 re52 [NFkB:IkB_alpha] → [NFkB];  
 
 re53 [IKKn] → [sa19_degraded];  
 
 re56 [IKKa] → [sa20_degraded];  
 
 re57 [IKKa:IKB_alpha] → [IKKa];  
 
 re58 [IKKa] + [NFkB:IkB_alpha] → [NFkB:IKKa:Ikb_alpha];  
 
 re59 [NFkB:IKKa:Ikb_alpha] → [NFkB] + [IKKa];  
 
 re60 [IKKi] → [sa444_degraded];  
 
 re61 [mRNAA20] → [A20] + [mRNAA20];  
 
 re62 [p50] + [p65] → [NFkB];  
 
 re63 [IKKa] → [IKKi];   {A20}
 
 re64 [IKK] → [IKKn];  
 
 re65 [IkB_alpha] + [NFkB] → [NFkB:IkB_alpha];  
 
 re66 [IkB_alpha] + [IKKa] → [IKKa:IKB_alpha];  
 
 re67 [NFkB] → 5.0 × [NFkB];  
 
 re68 5.0 × [NFkB:IkB_alpha] → [NFkB:IkB_alpha];  
 
 re69 [NFkB] + [IkB_alpha] → [NFkB:IkB_alpha];  
 
 re70 [mRNAA20] → [sa96_degraded];  
 
 re71 [A20] → [sa97_degraded];  
 
 re72 [IkB_alpha] → 5.0 × [IkB_alpha];  
 
 re74 [NFkB] → [csa21_degraded];  
 
 re75 [NFkB:IkB_alpha] → [csa18_degraded];  
 
 re76 [NFkB:IkB_alpha] → [csa9_degraded];  
 
Events (1)
 
 signal
k1 = 0.0025
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 sa4_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 p105
Compartment: default
Initial amount: 0.0
 
 sa438_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 sa3_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 mRNAp105
Compartment: default
Initial amount: 0.0
 
 p50
Compartment: default
Initial amount: 0.0
 
 mRNAp65
Compartment: default
Initial amount: 0.0
 
 sa8_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 p65
Compartment: default
Initial amount: 0.0
 
 sa9_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 sa13_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 IkB_alpha
Compartment: default
Initial amount: 0.0
 
 sa12_degraded
Compartment: default
Initial amount: 0.0
 
 mRNAA20
Compartment: default
Initial amount: 0.0
 
 A20
Compartment: default
Initial amount: 0.0
 
 sa444_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 IKKi
Compartment: default
Initial amount: 0.0
 
 sa19_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 IKKa
Compartment: default
Initial amount: 0.0
 
 IKKn
Compartment: default
Initial amount: 0.0
 
 sa20_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 sa96_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 sa97_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 csa21_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 csa18_degraded
Compartment: default
Initial amount: 0.0
Constant
 
 mRNAIKB_alpha
Compartment: default
Initial amount: 0.0
 
 NFkB:IkB_alpha
Compartment: default
Initial amount: 0.0
 
 NFkB:IKKa:Ikb_alpha
Compartment: default
Initial amount: 0.0
 
 NFkB
Compartment: default
Initial amount: 0.0
 
 IKKa:IKB_alpha
Compartment: default
Initial amount: 0.0
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 FTAx
Compartment: nucleus
Initial amount: 3.33333333333333E-4
 
 FTAy
Compartment: nucleus
Initial amount: 3.33333333333333E-4
 
 FTAz
Compartment: nucleus
Initial amount: 3.33333333333333E-4
 
 IkB_alpha
Compartment: nucleus
Initial amount: 0.0
 
 csa17_degraded
Compartment: nucleus
Initial amount: 0.0
Constant
 
 A20
Compartment: nucleus
Initial amount: 0.0
 
 IKK
Compartment: nucleus
Initial amount: 0.0
 
 csa9_degraded
Compartment: nucleus
Initial amount: 0.0
Constant
 
 InactivePRaseonp65
Compartment: nucleus
Initial amount: 0.0
 
 ActivePRaseonp65
Compartment: nucleus
Initial amount: 0.0
 
 InactivePRaseonp105
Compartment: nucleus
Initial amount: 0.0
 
 ActivePRaseonp105
Compartment: nucleus
Initial amount: 0.0
 
 ActivePRaseonIkB_alpha
Compartment: nucleus
Initial amount: 0.0
 
 NFkB:IkB_alpha
Compartment: nucleus
Initial amount: 0.0
 
 Promp65:RNAP2
Compartment: nucleus
Initial amount: 6.66666666666667E-6
 
 Promp65:RNAP2:FTAy
Compartment: nucleus
Initial amount: 0.0
 
 NFkB
Compartment: nucleus
Initial amount: 0.0
 
 Promp105:RNAP1:p50p65
Compartment: nucleus
Initial amount: 0.0
 
 Promp105:RNAP1:p50p65:IkBa
Compartment: nucleus
Initial amount: 0.0
 
 Promp105:RNAP
Compartment: nucleus
Initial amount: 6.66666666666667E-6
 
 Promp105:RNAP:FTAX
Compartment: nucleus
Initial amount: 0.0
 
 Promp105:RNAP1:FTAx:p50p65
Compartment: nucleus
Initial amount: 0.0
 
 Promp105:RNAP1:FTAx:p50p65:IkBa
Compartment: nucleus
Initial amount: 0.0
 
 PromIkBa:RNAP3
Compartment: nucleus
Initial amount: 6.66666666666667E-6
 
 PromIkBa:RNAP3:FTAz
Compartment: nucleus
Initial amount: 0.0
 
 InactivePRaseonIkB_alpha
Compartment: nucleus
Initial amount: 0.0
 
 PromIkBa:RNAP3:p50p65
Compartment: nucleus
Initial amount: 0.0
 
 PromIkBa:RNAP3:p50p65:IkBa
Compartment: nucleus
Initial amount: 0.0
 
 IkBa:RNAP3:FTAz:p50p65
Compartment: nucleus
Initial amount: 0.0
 
 PromIkBa:RNAP3:FTAz:p50p65:IkB_alpha
Compartment: nucleus
Initial amount: 0.0
 
Global Parameters (88)
 
   k1  
 
   k2
Value: 1.25E-4
Constant
 
   k3
Value: 1.0E-5
Constant
 
   k4
Value: 0.1
Constant
 
   k5
Value: 0.0015
Constant
 
   k6
Value: 1.25E-4
Constant
 
   k7
Value: 0.24
Constant
 
   k8
Value: 0.1
Constant
 
   k9
Value: 1.2
Constant
 
   k10
Value: 0.1
Constant
 
   k11
Value: 1.25E-4
Constant
 
   k12
Value: 2.0E-5
Constant
 
   kf13
Value: 0.5
Constant
 
   kr13
Constant
 
   kf14
Value: 0.5
Constant
 
   kr14
Constant
 
   kf15
Value: 0.0025
Constant
 
   kr15
Value: 8.0E-5
Constant
 
   k16
Value: 0.5
Constant
 
   k17
Value: 4.0E-4
Constant
 
   k18
Value: 3.0E-4
Constant
 
   k20
Value: 5.0E-7
Constant
 
   k19
Constant
 
   k21
Value: 1.0E-4
Constant
 
   k22
Value: 0.5
Constant
 
   kf23
Value: 0.0010
Constant
 
   kr23
Value: 5.0E-4
Constant
 
   k25
Constant
 
   k27
Value: 4.0E-4
Constant
 
   kf28
Value: 0.01
Constant
 
   kr28
Constant
 
   kf32
Value: 10.0
Constant
 
   kr32
Value: 1.0E-4
Constant
 
   k42
Value: 5.0E-4
Constant
 
   k43
Value: 0.1
Constant
 
   k33
Value: 5.0E-4
Constant
 
   k34
Value: 0.1
Constant
 
   k69
Value: 0.0060
Constant
 
   k70
Value: 0.06
Constant
 
   k49
Value: 5.0E-4
Constant
 
   k50
Value: 0.02
Constant
 
   k61
Value: 0.06
Constant
 
   k62
Value: 0.6
Constant
 
   k35
Value: 0.01
Constant
 
   k36
Value: 0.0041
Constant
 
   k37
Value: 5.0E-5
Constant
 
   k38
Value: 6.0E-5
Constant
 
   k39
Value: 1.3E-4
Constant
 
   k40
Value: 6.4E-5
Constant
 
   kf41
Value: 10.0
Constant
 
   kr41
Value: 1.0E-4
Constant
 
   k44
Value: 0.016
Constant
 
   k45
Value: 0.0053
Constant
 
   k46
Value: 5.0E-5
Constant
 
   k47
Value: 6.4E-5
Constant
 
   kf48
Value: 10.0
Constant
 
   kr48
Value: 1.0E-4
Constant
 
   k51
Value: 0.025
Constant
 
   kf52
Value: 0.0030
Constant
 
   kr52
Value: 0.0010
Constant
 
   k53
Value: 2.0E-4
Constant
 
   k54
Value: 2.0E-4
Constant
 
   kf55
Value: 0.62
Constant
 
   kr55
Value: 4.8E-4
Constant
 
   kf56
Value: 0.62
Constant
 
   kr56
Value: 4.8E-4
Constant
 
   kf57
Value: 18.4
Constant
 
   kr57
Value: 0.055
Constant
 
   kf58
Value: 18.4
Constant
 
   kr58
Value: 0.055
Constant
 
   kf59
Value: 0.0038
Constant
 
   kr59
Value: 8.0E-13
Constant
 
   kf60
Value: 0.0038
Constant
 
   kr60
Value: 8.0E-13
Constant
 
   kf63
Value: 0.62
Constant
 
   kr63
Value: 4.8E-4
Constant
 
   kf64
Value: 0.62
Constant
 
   kr64
Value: 4.8E-4
Constant
 
   kf65
Value: 18.4
Constant
 
   kr65
Value: 0.055
Constant
 
   kf66
Value: 18.4
Constant
 
   kr66
Value: 0.055
Constant
 
   kf67
Value: 0.0038
Constant
 
   kr67
Value: 8.0E-13
Constant
 
   kf68
Value: 0.0038
Constant
 
   kr68
Value: 8.0E-13
Constant
 
   k71
Value: 2.0E-4
Constant
 
   k72
Value: 2.0E-4
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000227

Curator's comment: (updated: 07 Aug 2009 11:41:41 BST)

Figure 7c (M(39,65,90)) of the reference publication is reproduced. The model was integrated and simulated using Mathematica 6.0 - MathSBML 2.7.1.

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