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BIOMD0000000230 - Ihekwaba2004_NFkB_Sensitivity

 

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Reference Publication
Publication ID: 17052119
Ihekwaba AE, Broomhead DS, Grimley RL, Benson N, Kell DB.
Sensitivity analysis of parameters controlling oscillatory signalling in the NF-kappaB pathway: the roles of IKK and IkappaBalpha.
Syst Biol (Stevenage) 2004 Jun; 1(1): 93-103
Department of Chemistry, UMIST, Manchester UK.  [more]
Model
Original Model: JWS logo
Submitter: Lukas Endler
Submission ID: MODEL5952988280
Submission Date: 25 Jun 2009 19:03:10 UTC
Last Modification Date: 09 Aug 2012 16:31:24 UTC
Creation Date: 19 Aug 2009 13:05:41 UTC
Encoders:  Vijayalakshmi Chelliah
   Adaoha EC Ihekwaba
set #1
bqbiol:occursIn Taxonomy Mus musculus
bqbiol:isVersionOf BioModels Database Hoffmann2002_KnockOut_IkBNFkB_Signaling
bqbiol:isPartOf KEGG Pathway mmu04660
set #2
bqbiol:isVersionOf Gene Ontology I-kappaB kinase/NF-kappaB signaling
Notes

This a model from the article:
Sensitivity analysis of parameters controlling oscillatory signalling in the NF-kappaB pathway: the roles of IKK and IkappaBalpha.
Ihekwaba AE, Broomhead DS, Grimley RL, Benson N, Kell DB Syst Biol (Stevenage) [2004 Jun;1(1):93-103 17052119 ,
Abstract:
Analysis of cellular signalling interactions is expected to create an enormous informatics challenge, perhaps even greater than that of analysing the genome. A key step in the evolution towards a more quantitative understanding of signalling is to specify explicitly the kinetics of all chemical reaction steps in a pathway. We have reconstructed a model of the nuclear factor, kappaB (NF-kappaB) signalling pathway, containing 64 parameters and 26 variables, including steps in which the activation of the NF-kappaB transcription factor is intimately associated with the phosphorylation and ubiquitination of its inhibitor kappaB by a membrane-associated kinase, and its translocation from the cytoplasm to the nucleus. We apply sensitivity analysis to the model. This identifies those parameters in this (IkappaB)/NF-kappaB signalling system (containing only induced IkappaBalpha isoform) that most affect the oscillatory concentration of nuclear NF-kappaB (in terms of both period and amplitude). The intention is to provide guidance on which proteins are likely to be most significant as drug targets or should be exploited for further, more detailed experiments. The sensitivity coefficients were found to be strongly dependent upon the magnitude of the parameter change studied, indicating the highly non-linear nature of the system. Of the 64 parameters in the model, only eight to nine exerted a major control on nuclear NF-kappaB oscillations, and each of these involved as reaction participants either the IkappaB kinase (IKK) or IkappaBalpha, directly. This means that the dominant dynamics of the pathway can be reflected, in addition to that of nuclear NF-kappaB itself, by just two of the other pathway variables. This is conveniently observed in a phase-plane plot.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.

To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 17052119 Submission Date: 25 Jun 2009 19:03:10 UTC Last Modification Date: 09 Aug 2012 16:31:24 UTC Creation Date: 19 Aug 2009 13:05:41 UTC
Mathematical expressions
Reactions
v1 v2 v3 v4
v5 v6 v7 v8
v9 v10 v11 v12
v13 v14 v15 v16
v17 v18 v19 v20
v21 v22 v23 v24
v25 v26 v27 v28
v29 v30 v31 v32
v33 v34 v35 v36
v37 v38 v39 v40
v41 v42 v43 v44
v45 v46 v47 v48
v49 v50 v51 v52
v53 v54 v55 v56
v57 v58 v59 v60
v61 v62 v63 v64
Physical entities
Compartments Species
compartment NFkB IKKIkBa IKKIkBaNFkB
IKK IkBa IKKIkBb
IKKIkBbNFkB IkBb IKKIkBe
IKKIkBeNFkB IkBe IkBaNFkB
IkBbNFkB IkBeNFkB source
IkBat sink NFkBn
IkBan IkBanNFkBn IkBbn
IkBbnNFkBn IkBbt IkBen
IkBenNFkBn IkBet  
Global parameters
k1 k2 k3 k4
k5 k6 k7 k8
k9 k10 k11 k12
k13 k14 k15 k16
k17 k18 k19 k20
k21 k22 k23 k24
k25 k26 k27 k28
k29 k30 k31 k32
k33 k34 k35 k36
k37 k38 k39 k40
k41 k42 k43 k44
k45 k46 k47 k48
k49 k50 k51 k52
k53 k54 k55 k56
k57 k58 k59 k60
k61 k62 k63 k64
Reactions (64)
 
 v1 [NFkB] + [IKKIkBa] → [IKKIkBaNFkB];  
 
 v2 [IKKIkBaNFkB] → [NFkB] + [IKK];  
 
 v3 [IKKIkBaNFkB] → [NFkB] + [IKKIkBa];  
 
 v4 [IKK] + [IkBa] → [IKKIkBa];  
 
 v5 [IKKIkBa] → [IKK];  
 
 v6 [IKKIkBa] → [IKK] + [IkBa];  
 
 v7 [IKKIkBb] + [NFkB] → [IKKIkBbNFkB];  
 
 v8 [IKKIkBbNFkB] → [IKK] + [NFkB];  
 
 v9 [IKKIkBbNFkB] → [IKKIkBb] + [NFkB];  
 
 v10 [IkBb] + [IKK] → [IKKIkBb];  
 
 v11 [IKKIkBb] → [IKK];  
 
 v12 [IKKIkBb] → [IKK] + [IkBb];  
 
 v13 [NFkB] + [IKKIkBe] → [IKKIkBeNFkB];  
 
 v14 [IKKIkBeNFkB] → [NFkB] + [IKK];  
 
 v15 [IKKIkBeNFkB] → [NFkB] + [IKKIkBe];  
 
 v16 [IkBe] + [IKK] → [IKKIkBe];  
 
 v17 [IKKIkBe] → [IKK];  
 
 v18 [IKKIkBe] → [IkBe] + [IKK];  
 
 v19 [IkBaNFkB] + [IKK] → [IKKIkBaNFkB];  
 
 v20 [IKKIkBaNFkB] → [IkBaNFkB] + [IKK];  
 
 v21 [IkBbNFkB] + [IKK] → [IKKIkBbNFkB];  
 
 v22 [IKKIkBbNFkB] → [IkBbNFkB] + [IKK];  
 
 v23 [IKK] + [IkBeNFkB] → [IKKIkBeNFkB];  
 
 v24 [IKKIkBeNFkB] → [IKK] + [IkBeNFkB];  
 
 v25 [IkBa] + [NFkB] → [IkBaNFkB];  
 
 v26 2.0 × [source] → [IkBat] + 2.0 × [sink];   {NFkBn}
 
 v27 [IkBaNFkB] → [IkBa] + [NFkB];  
 
 v28 [NFkBn] + [IkBan] → [IkBanNFkBn];  
 
 v29 [IkBanNFkBn] → [NFkBn] + [IkBan];  
 
 v30 [IkBanNFkBn] → [IkBaNFkB];  
 
 v31 [IkBaNFkB] → [NFkB];  
 
 v32 [IkBat] → [sink];  
 
 v33 [IkBan] → [IkBa];  
 
 v34 [IkBa] → [IkBan];  
 
 v35 [source] → [IkBa] + [sink];   {IkBat}
 
 v36 [IkBb] + [NFkB] → [IkBbNFkB];  
 
 v37 [IkBbNFkB] → [IkBb] + [NFkB];  
 
 v38 [IkBbn] + [NFkBn] → [IkBbnNFkBn];  
 
 v39 [IkBbnNFkBn] → [IkBbn] + [NFkBn];  
 
 v40 [IkBbnNFkBn] → [IkBbNFkB];  
 
 v41 [IkBbNFkB] → [NFkB];  
 
 v42 [IkBbt] → [sink];  
 
 v43 [IkBbn] → [IkBb];  
 
 v44 [IkBb] → [IkBbn];  
 
 v45 [source] → [IkBb] + [sink];   {IkBbt}
 
 v46 [NFkB] + [IkBe] → [IkBeNFkB];  
 
 v47 [IkBeNFkB] → [NFkB] + [IkBe];  
 
 v48 [NFkBn] + [IkBen] → [IkBenNFkBn];  
 
 v49 [IkBenNFkBn] → [IkBen] + [NFkBn];  
 
 v50 [IkBenNFkBn] → [IkBeNFkB];  
 
 v51 [IkBeNFkB] → [NFkB];  
 
 v52 [IkBet] → [sink];  
 
 v53 [IkBen] → [IkBe];  
 
 v54 [IkBe] → [IkBen];  
 
 v55 [source] → [IkBe] + [sink];   {IkBet}
 
 v56 [NFkBn] → [NFkB];  
 
 v57 [NFkB] → [NFkBn];  
 
 v58 [source] → [IkBat];  
 
 v59 [source] → [IkBbt];  
 
 v60 [source] → [IkBet];  
 
 v61 [IkBa] → [sink];  
 
 v62 [IkBb] → [sink];  
 
 v63 [IkBe] → [sink];  
 
 v64 [IKK] → [sink];  
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 NFkB
Compartment: compartment
Initial concentration: 2.5081E-4
 
 IKKIkBa
Compartment: compartment
Initial concentration: 0.0
 
 IKKIkBaNFkB
Compartment: compartment
Initial concentration: 0.0
 
 IKK
Compartment: compartment
Initial concentration: 0.1
 
 IkBa
Compartment: compartment
Initial concentration: 0.19028
 
 IKKIkBb
Compartment: compartment
Initial concentration: 0.0
 
 IKKIkBbNFkB
Compartment: compartment
Initial concentration: 0.0
 
 IkBb
Compartment: compartment
Initial concentration: 0.021428
 
 IKKIkBe
Compartment: compartment
Initial concentration: 0.0
 
 IKKIkBeNFkB
Compartment: compartment
Initial concentration: 0.0
 
 IkBe
Compartment: compartment
Initial concentration: 0.015307
 
 IkBaNFkB
Compartment: compartment
Initial concentration: 0.082062
 
 IkBbNFkB
Compartment: compartment
Initial concentration: 0.0090963
 
 IkBeNFkB
Compartment: compartment
Initial concentration: 0.0064977
 
   source
Compartment: compartment
Initial concentration: 1.0
Constant
 
   IkBat
Compartment: compartment
Initial concentration: 0.0054868
 
   sink
Compartment: compartment
Initial concentration: 0.0
Constant
 
 NFkBn
Compartment: compartment
Initial concentration: 2.0366E-4
 
 IkBan
Compartment: compartment
Initial concentration: 0.19326
 
 IkBanNFkBn
Compartment: compartment
Initial concentration: 0.0013739
 
 IkBbn
Compartment: compartment
Initial concentration: 0.021887
 
 IkBbnNFkBn
Compartment: compartment
Initial concentration: 3.0061E-4
 
   IkBbt
Compartment: compartment
Initial concentration: 6.3696E-4
 
 IkBen
Compartment: compartment
Initial concentration: 0.015635
 
 IkBenNFkBn
Compartment: compartment
Initial concentration: 2.1473E-4
 
   IkBet
Compartment: compartment
Initial concentration: 4.55E-4
 
Global Parameters (64)
 
   k1
Value: 0.5
Constant
 
   k2
Value: 5.0E-4
Constant
 
   k3
Value: 0.5
Constant
 
   k4
Value: 5.0E-4
Constant
 
   k5
Value: 0.5
Constant
 
   k6
Value: 5.0E-4
Constant
 
   k7
Value: 0.5
Constant
 
   k8
Value: 5.0E-4
Constant
 
   k9
Value: 0.0204
Constant
 
   k10
Value: 0.5
Constant
 
   k11
Value: 5.0E-4
Constant
 
   k12
Value: 0.0075
Constant
 
   k13
Value: 0.5
Constant
 
   k14
Value: 5.0E-4
Constant
 
   k15
Value: 0.011
Constant
 
   k16
Value: 2.25E-5
Constant
 
   k17
Value: 2.25E-5
Constant
 
   k18
Value: 2.25E-5
Constant
 
   k19
Value: 0.09
Constant
 
   k20
Value: 8.0E-5
Constant
 
   k21
Value: 0.5
Constant
 
   k22
Value: 5.0E-4
Constant
 
   k23
Value: 0.5
Constant
 
   k24
Value: 5.0E-4
Constant
 
   k25
Value: 0.5
Constant
 
   k26
Value: 5.0E-4
Constant
 
   k27
Value: 1.54E-6
Constant
 
   k28
Value: 0.0165
Constant
 
   k29
Value: 2.8E-4
Constant
 
   k30
Value: 1.78E-7
Constant
 
   k31
Value: 2.8E-4
Constant
 
   k32
Value: 1.27E-7
Constant
 
   k33
Value: 2.8E-4
Constant
 
   k34
Value: 0.0225
Constant
 
   k35
Value: 0.00125
Constant
 
   k36
Value: 0.00408
Constant
 
   k37
Value: 1.13E-4
Constant
 
   k38
Value: 3.0E-4
Constant
 
   k39
Value: 2.0E-4
Constant
 
   k40
Value: 0.0060
Constant
 
   k41
Value: 0.00175
Constant
 
   k42
Value: 0.00408
Constant
 
   k43
Value: 1.13E-4
Constant
 
   k44
Value: 1.5E-4
Constant
 
   k45
Value: 1.0E-4
Constant
 
   k46
Value: 0.0090
Constant
 
   k47
Value: 0.00175
Constant
 
   k48
Value: 0.00408
Constant
 
   k49
Value: 1.13E-4
Constant
 
   k50
Value: 1.5E-4
Constant
 
   k51
Value: 1.0E-4
Constant
 
   k52
Value: 0.185
Constant
 
   k53
Value: 0.00125
Constant
 
   k54
Value: 0.0138
Constant
 
   k55
Value: 0.048
Constant
 
   k56
Value: 0.00175
Constant
 
   k57
Value: 0.0052
Constant
 
   k58
Value: 0.07
Constant
 
   k59
Value: 0.00175
Constant
 
   k60
Value: 0.0052
Constant
 
   k61
Value: 1.2E-4
Constant
 
   k62
Value: 0.00407
Constant
 
   k63
Value: 0.0015
Constant
 
   k64
Value: 0.0022
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000230

Curator's comment: (updated: 19 Aug 2009 14:17:57 BST)

The model reproduces, Figure 5 (Time course of nuclear NFkb (NFkBn) and Figure 9 (Time dependent relationship between the concentrations of IKK, IkBa and NFkBn) of the reference publication. The model was integrated and simulated using Copasi v4.5 (Build 30).

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