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BIOMD0000000303 - Liu2011_Complement_System

 

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Reference Publication
Publication ID: 21283780
Liu B, Zhang J, Tan PY, Hsu D, Blom AM, Leong B, Sethi S, Ho B, Ding JL, Thiagarajan PS.
A computational and experimental study of the regulatory mechanisms of the complement system.
PLoS Comput. Biol. 2011; 7(1): e1001059
School of Computing, National University of Singapore, Singapore.  [more]
Model
Original Model: BIOMD0000000303.xml.origin
Submitter: Lukas Endler
Submission ID: MODEL1101260000
Submission Date: 26 Jan 2011 04:24:09 UTC
Last Modification Date: 27 Feb 2011 23:31:52 UTC
Creation Date: 26 Jan 2011 16:04:44 UTC
Encoders:  Lukas Endler
   Bing Liu
set #1
bqbiol:occursIn Taxonomy Homo sapiens
bqbiol:isVersionOf Reactome REACT_6932.3
Gene Ontology complement activation
bqbiol:hasVersion Gene Ontology complement activation, lectin pathway
Gene Ontology complement activation, classical pathway
set #2
bqbiol:isPartOf KEGG Pathway hsa04610
Notes
Model of the Complement System

This is the continuous deterministic (ODE) model of the complement system described in the article:
Computational and Experimental Study of the Regulatory Mechanisms of the Complement System.
Liu B, Zhang J, Tan PY, Hsu D, Blom AM, Leong B, Sethi S, Ho B, Ding JL and Thiagarajan PS. PLoS Comp. Bio. 2011 Jan. 7:1; doi: 10.1371/journal.pcbi.1001059

Abstract:
The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.

Comment:
Reproduction of figures in the article:
Figure 5: the effects of C4BP
Fig 5A: set initial concentrations PC=0.0327796, GlcNac=0, vary the initial concentration of C4BP from 2.6 to 2600 using parameter scan
Fig 5B: set initial concentrations PC=0, GlcNac=0.0327796, vary the initial concentration of C4BP from 2.6 to 2600 using parameter scan
Figure 6: knockout simulations
Set PC=0.0327796, GlcNac=0
Fig 6A: kf01=0, kf02=0
Fig 6B: kf04=0, kf06=0, kf07=0
Fig 6C: kf05=0
Fig 6D: kf03=0

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use .
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: 21283780 Submission Date: 26 Jan 2011 04:24:09 UTC Last Modification Date: 27 Feb 2011 23:31:52 UTC Creation Date: 26 Jan 2011 16:04:44 UTC
Mathematical expressions
Reactions
a_01 a_02 a_03 a_04
c_01 c_02 c_03 c_04
d_01 d_02 d_03 d_04
b_01 b_02 b_03 b_04
e_01 e_02 e_03 e_04
f_01 f_02 f_03 f_04
f_05 f_06 f_07 t_01
t_02 t_03 d_05 d_06
d_07 t_04 e_05 e_06
e_07 d_08 d_09 d_10
d_11 g_01 g_02 g_03
g_04      
Rules
Assignment Rule (variable: mC3)      
Physical entities
Compartments Species
compartment CRP PC PC/CRP
C4 C4a C4b
C2 C1 PC/CRP/C1
C2a C2b C4b/C2a
C3 C3a C3b
dC3b MASP dC4b/C2a
GlcNac GlcNac/LF LF
GlcNac/LF/MASP PC/CRP/LF PC/CRP/LF/MASP
GlcNac/LF/CRP GlcNac/LF/CRP/C1 C4BP
C4BP/PC/CRP C4BP/GlcNac/LF/CRP iC4b/C2a
C4BP/C4b C4b/C2a/C4BP dC4b/C2a/C4BP
PC/CRP/LF/C1 C4BP/PC/CRP/LF GlcNac/LF/CRP/MASP
PC/CRP/LF/C1/MASP GlcNac/LF/C1/MASP GlcNac/HF
HF GlcNac/HF/MASP X
Global parameters
ka01_1 ka01_2 ka02_1 ka02_2
ka03_1 ka04_1 kc01_1 kc01_2
kc02 kc03_1 kc03_2 kc04_1
ka03_2 ka04_2 kd02_2 kd02_1
kd03_1 kd03_2 kb01_1 kb01_2
kb02_1 kb02_2 kb03_1 kb03_2
kb04_1 kb04_2 kc04_2 kd01_1
kd01_2 kd04_1 kd04_2 ke01_1
ke01_2 ke02_1 ke02_2 ke03_1
ke03_2 ke04_1 ke04_2 kf01_1
kf01_2 kf02_1 kf02_2 kf03
kf04_2 kf04_1 kf05 mC3
kf06_1 kf06_2 kf07_1 kf07_2
kd05_1 kd05_2 kd06_1 kd06_2
kd07_1 kd07_2 ke05_1 ke05_2
ke06_1 ke06_2 ke07_1 ke07_2
kd08_1 kd08_2 kd09_1 kd09_2
kd10_1 kd10_2 kd11_1 kd11_2
kg01_1 kg01_2 kg02_1 kg02_2
kg03_1 kg03_2 kg04_1 kg04_2
kt01 kt02 kt03 kt04_1
kt04_2      
Reactions (45)
 
 a_01 [PC] + [CRP] ↔ [PC/CRP];  
 
 a_02 [PC/CRP] + [C1] ↔ [PC/CRP/C1];  
 
 a_03 [C4] → [C4a] + [C4b];   {PC/CRP/C1}
 
 a_04 [C2] → [C2a] + [C2b];   {PC/CRP/C1}
 
 c_01 [C4b] + [C2a] ↔ [C4b/C2a];  
 
 c_02 [C4b/C2a] + [C3] → [C4b/C2a] + [C3a] + [C3b];  
 
 c_03 [C3b] ↔ [dC3b];  
 
 c_04 [C4b/C2a] ↔ [dC4b/C2a];  
 
 d_01 [PC/CRP] + [LF] ↔ [PC/CRP/LF];  
 
 d_02 [PC/CRP/LF] + [MASP] ↔ [PC/CRP/LF/MASP];  
 
 d_03 [C4] → [C4a] + [C4b];   {PC/CRP/LF/MASP}
 
 d_04 [C2] → [C2a] + [C2b];   {PC/CRP/LF/MASP}
 
 b_01 [GlcNac] + [LF] ↔ [GlcNac/LF];  
 
 b_02 [GlcNac/LF] + [MASP] ↔ [GlcNac/LF/MASP];  
 
 b_03 [C4] → [C4a] + [C4b];   {GlcNac/LF/MASP}
 
 b_04 [C2] → [C2a] + [C2b];   {GlcNac/LF/MASP}
 
 e_01 [GlcNac/LF] + [CRP] ↔ [GlcNac/LF/CRP];  
 
 e_02 [GlcNac/LF/CRP] + [C1] ↔ [GlcNac/LF/CRP/C1];  
 
 e_03 [C4] → [C4a] + [C4b];   {GlcNac/LF/CRP/C1}
 
 e_04 [C2] → [C2a] + [C2b];   {GlcNac/LF/CRP/C1}
 
 f_01 [C4BP] + [PC/CRP] ↔ [C4BP/PC/CRP];  
 
 f_02 [C4BP] + [GlcNac/LF/CRP] ↔ [C4BP/GlcNac/LF/CRP];  
 
 f_03 [C4b/C2a] + [C4BP] → [iC4b/C2a] + [C4BP];  
 
 f_04 [C4BP] + [C4b] ↔ [C4BP/C4b];  
 
 f_05 [C4b/C2a] + [C4BP] → [C4b] + [C2a] + [C4BP];  
 
 f_06 [C4b/C2a] + [C4BP] ↔ [C4b/C2a/C4BP];  
 
 f_07 [dC4b/C2a] + [C4BP] ↔ [dC4b/C2a/C4BP];  
 
 t_01 [C4BP] → ;  
 
 t_02 [C3b] → ;  
 
 t_03 [C4b/C2a] → ;  
 
 d_05 [PC/CRP/LF] + [C1] ↔ [PC/CRP/LF/C1];  
 
 d_06 [C4] → [C4a] + [C4b];   {PC/CRP/LF/C1}
 
 d_07 [C2] → [C2a] + [C2b];   {PC/CRP/LF/C1}
 
 t_04 [C4BP] + [PC/CRP/LF] ↔ [C4BP/PC/CRP/LF];  
 
 e_05 [GlcNac/LF/CRP] + [MASP] ↔ [GlcNac/LF/CRP/MASP];  
 
 e_06 [C4] → [C4a] + [C4b];   {GlcNac/LF/CRP/MASP}
 
 e_07 [C2] → [C2a] + [C2b];   {GlcNac/LF/CRP/MASP}
 
 d_08 [PC/CRP/LF/C1] + [MASP] ↔ [PC/CRP/LF/C1/MASP];  
 
 d_09 [PC/CRP/LF/MASP] + [C1] ↔ [PC/CRP/LF/C1/MASP];  
 
 d_10 [C4] → [C4a] + [C4b];   {PC/CRP/LF/C1/MASP}
 
 d_11 [C2] → [C2a] + [C2b];   {PC/CRP/LF/C1/MASP}
 
 g_01 [X] + [HF] ↔ [GlcNac/HF];  
 
 g_02 [GlcNac/HF] + [MASP] ↔ [GlcNac/HF/MASP];  
 
 g_03 [C4] → [C4a] + [C4b];   {GlcNac/HF/MASP}
 
 g_04 [C2] → [C2a] + [C2b];   {GlcNac/HF/MASP}
 
Rules (1)
 
 Assignment Rule (name: mC3) mC3 = dC3b
 
Functions (1)
 
 my-MM lambda(k, E, S, Km, k*E*S/(Km+S))
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 CRP
Compartment: compartment
Initial concentration: 2.0
 
 PC
Compartment: compartment
Initial concentration: 0.0327796
 
 PC/CRP
Compartment: compartment
Initial concentration: 0.0
 
 C4
Compartment: compartment
Initial concentration: 770.0
 
 C4a
Compartment: compartment
Initial concentration: 0.0
 
 C4b
Compartment: compartment
Initial concentration: 0.0
 
 C2
Compartment: compartment
Initial concentration: 310.0
 
 C1
Compartment: compartment
Initial concentration: 2470.0
 
 PC/CRP/C1
Compartment: compartment
Initial concentration: 0.0
 
 C2a
Compartment: compartment
Initial concentration: 0.0
 
 C2b
Compartment: compartment
Initial concentration: 0.0
 
 C4b/C2a
Compartment: compartment
Initial concentration: 0.0
 
 C3
Compartment: compartment
Initial concentration: 4650.0
 
 C3a
Compartment: compartment
Initial concentration: 0.0
 
 C3b
Compartment: compartment
Initial concentration: 0.0
 
 dC3b
Compartment: compartment
Initial concentration: 0.0
 
 MASP
Compartment: compartment
Initial concentration: 6.8
 
 dC4b/C2a
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/LF
Compartment: compartment
Initial concentration: 0.0
 
 LF
Compartment: compartment
Initial concentration: 20.0
 
 GlcNac/LF/MASP
Compartment: compartment
Initial concentration: 0.0
 
 PC/CRP/LF
Compartment: compartment
Initial concentration: 0.0
 
 PC/CRP/LF/MASP
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/LF/CRP
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/LF/CRP/C1
Compartment: compartment
Initial concentration: 0.0
 
 C4BP
Compartment: compartment
Initial concentration: 260.0
 
 C4BP/PC/CRP
Compartment: compartment
Initial concentration: 0.0
 
 C4BP/GlcNac/LF/CRP
Compartment: compartment
Initial concentration: 0.0
 
 iC4b/C2a
Compartment: compartment
Initial concentration: 0.0
 
 C4BP/C4b
Compartment: compartment
Initial concentration: 0.0
 
 C4b/C2a/C4BP
Compartment: compartment
Initial concentration: 0.0
 
 dC4b/C2a/C4BP
Compartment: compartment
Initial concentration: 0.0
 
 PC/CRP/LF/C1
Compartment: compartment
Initial concentration: 0.0
 
 C4BP/PC/CRP/LF
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/LF/CRP/MASP
Compartment: compartment
Initial concentration: 0.0
 
 PC/CRP/LF/C1/MASP
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/LF/C1/MASP
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/HF
Compartment: compartment
Initial concentration: 0.0
 
 HF
Compartment: compartment
Initial concentration: 0.0
 
 GlcNac/HF/MASP
Compartment: compartment
Initial concentration: 0.0
 
 X
Compartment: compartment
Initial concentration: 5.0E-4
 
Global Parameters (85)
 
 ka01_1
Value: 0.0275999
Constant
 
 ka01_2
Value: 0.0109
Constant
 
 ka02_1
Value: 7.4E-4
Constant
 
 ka02_2
Value: 0.0011
Constant
 
 ka03_1
Value: 2.0
Constant
 
 ka04_1
Value: 10.5
Constant
 
 kc01_1
Value: 0.64564661669102
Constant
 
 kc01_2
Value: 0.194551104058408
Constant
 
 kc02
Value: 5.91152775857994E-4
Constant
 
 kc03_1
Value: 0.414004459949002
Constant
 
 kc03_2
Value: 0.99647572245388
Constant
 
 kc04_1
Value: 0.977836567576895
Constant
 
 ka03_2
Value: 500.0
Constant
 
 ka04_2
Value: 2500.0
Constant
 
 kd02_2
Value: 0.1
Constant
 
 kd02_1
Value: 0.0368010796682635
Constant
 
 kd03_1
Value: 66.3776807395383
Constant
 
 kd03_2
Value: 829.115813389061
Constant
 
 kb01_1
Value: 0.091011109910329
Constant
 
 kb01_2
Value: 0.0508205528375529
Constant
 
 kb02_1
Value: 0.0368010796682635
Constant
 
 kb02_2
Value: 0.1
Constant
 
 kb03_1
Value: 66.3776807395383
Constant
 
 kb03_2
Value: 829.115813389061
Constant
 
 kb04_1
Value: 1.1
Constant
 
 kb04_2
Value: 2000.0
Constant
 
 kc04_2
Value: 0.199162432258527
Constant
 
 kd01_1
Value: 7.07E-5
Constant
 
 kd01_2
Value: 7.23E-5
Constant
 
 kd04_1
Value: 1.1
Constant
 
 kd04_2
Value: 2000.0
Constant
 
 ke01_1
Value: 7.07E-5
Constant
 
 ke01_2
Value: 1.0E-4
Constant
 
 ke02_1
Value: 7.4E-4
Constant
 
 ke02_2
Value: 0.0011
Constant
 
 ke03_1
Value: 2.0
Constant
 
 ke03_2
Value: 500.0
Constant
 
 ke04_1
Value: 10.5
Constant
 
 ke04_2
Value: 2500.0
Constant
 
 kf01_1
Value: 0.969998277173144
Constant
 
 kf01_2
Value: 0.069020578737621
Constant
 
 kf02_1
Value: 0.969998277173144
Constant
 
 kf02_2
Value: 0.069020578737621
Constant
 
 kf03
Value: 0.0613537204215846
Constant
 
 kf04_2
Value: 0.983691204042155
Constant
 
 kf04_1
Value: 0.613416050428938
Constant
 
 kf05
Value: 0.980777558937884
Constant
 
  mC3  
 
 kf06_1
Value: 0.613416050428938
Constant
 
 kf06_2
Value: 0.983691204042155
Constant
 
 kf07_1
Value: 0.613416050428938
Constant
 
 kf07_2
Value: 0.983691204042155
Constant
 
 kd05_1
Value: 7.4E-4
Constant
 
 kd05_2
Value: 0.0011
Constant
 
 kd06_1
Value: 2.0
Constant
 
 kd06_2
Value: 500.0
Constant
 
 kd07_1
Value: 10.5
Constant
 
 kd07_2
Value: 2500.0
Constant
 
 ke05_1
Value: 0.0368010796682635
Constant
 
 ke05_2
Value: 0.1
Constant
 
 ke06_1
Value: 66.3776807395383
Constant
 
 ke06_2
Value: 829.115813389061
Constant
 
 ke07_1
Value: 1.1
Constant
 
 ke07_2
Value: 2000.0
Constant
 
 kd08_1
Value: 0.0368010796682635
Constant
 
 kd08_2
Value: 0.1
Constant
 
 kd09_1
Value: 7.4E-4
Constant
 
 kd09_2
Value: 0.0011
Constant
 
 kd10_1
Value: 71.1705760475931
Constant
 
 kd10_2
Value: 3796.22684377655
Constant
 
 kd11_1
Value: 38.9625903487667
Constant
 
 kd11_2
Value: 5972.30640657865
Constant
 
 kg01_1
Value: 0.091011109910329
Constant
 
 kg01_2
Value: 0.0508205528375529
Constant
 
 kg02_1
Value: 0.0368010796682635
Constant
 
 kg02_2
Value: 0.1
Constant
 
 kg03_1
Value: 66.3776807395383
Constant
 
 kg03_2
Value: 829.115813389061
Constant
 
 kg04_1
Value: 1.1
Constant
 
 kg04_2
Value: 2000.0
Constant
 
 kt01
Value: 3.42266E-4
Constant
 
 kt02
Value: 0.492901
Constant
 
 kt03
Value: 0.0470911
Constant
 
 kt04_1
Constant
 
 kt04_2
Constant
 
t_01 (1)
 
   k1
Value: 3.42266E-4
Constant
 
t_02 (1)
 
   k1
Value: 0.492901
Constant
 
t_03 (1)
 
   k1
Value: 0.0470911
Constant
 
t_04 (2)
 
   k1
Constant
 
   k2
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000303

Curator's comment: (updated: 26 Jan 2011 04:34:09 GMT)

Reproduction of figure 5A of the reference publication. The time courses were integrated using SBML ODEsolver.

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