Mol2013 - Immune Signal Transduction in Leishmaniasis

  public model
Model Identifier
BIOMD0000000477
Short description

Created by The MathWorks, Inc. SimBiology tool, Version 3.3

Format
SBML (L2V4)
Related Publication
  • Immune signal transduction in leishmaniasis from natural to artificial systems: role of feedback loop insertion.
  • Mol M, Patole MS, Singh S
  • Biochimica et biophysica acta , 1/ 2014 , Volume 1840 , pages: 71-79 , PubMed ID: 23994140
  • National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune University Campus, Pune 411007, India.
  • Modulated immune signal (CD14-TLR and TNF) in leishmaniasis can be linked to EGFR pathway involved in wound healing, through crosstalk points. This signaling network can be further linked to a synthetic gene circuit acting as a positive feedback loop to elicit a synchronized intercellular communication among the immune cells which may contribute to a better understanding of signaling dynamics in leishmaniasis.Network reconstruction with positive feedback loop, simulation (ODE 15s solver) and sensitivity analysis of CD14-TLR, TNF and EGFR was done in SimBiology (MATLAB 7.11.1). Cytoscape and adjacency matrix were used to calculate network topology. PCA was extracted by using sensitivity coefficient in MATLAB. Model reduction was done using time, flux and sensitivity score.Network has five crosstalk points: NIK, IκB-NFκB and MKK (4/7, 3/6, 1/2) which show high flux and sensitivity. PI3K in EGFR pathway shows high flux and sensitivity. PCA score was high for cytoplasmic ERK1/2, PI3K, Atk, STAT1/3 and nuclear JNK. Of the 125 parameters, 20% are crucial as deduced by model reduction.EGFR can be linked to CD14-TLR and TNF through the MAPK crosstalk points. These pathways may be controlled through Ras and Raf that lie upstream of signaling components ERK ½ (c) and JNK (n) that have a high PCA score via a synthetic gene circuit for activating cell-cell communication to elicit an inflammatory response. Also a disease resolving effect may be achieved through PI3K in the EGFR pathway.The reconstructed signaling network can be linked to a gene circuit with a positive feedback loop, for cell-cell communication resulting in synchronized response in the immune cell population, for disease resolving effect in leishmaniasis.
Contributors
administrator, Shailza Singh

Metadata information

is
BioModels Database MODEL1308080000
BioModels Database BIOMD0000000477
isDescribedBy
PubMed 23994140
hasTaxon
Taxonomy Homo sapiens
hasPart
hasProperty
Human Disease Ontology leishmaniasis

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000477_url.xml SBML L2V4 representation of Mol2013 - Immune Signal Transduction in Leishmaniasis 116.58 KB Preview | Download

Additional files

BIOMD0000000477-biopax2.owl Auto-generated BioPAX (Level 2) 96.55 KB Preview | Download
BIOMD0000000477.png Auto-generated Reaction graph (PNG) 319.30 KB Preview | Download
BIOMD0000000477-biopax3.owl Auto-generated BioPAX (Level 3) 160.70 KB Preview | Download
BIOMD0000000477.xpp Auto-generated XPP file 22.34 KB Preview | Download
MODEL1308080000_figure5.cps Reaction fluxes of signalling components that are at the crosstalk point and that show high PCA score. 149.15 KB Preview | Download
BIOMD0000000477.m Auto-generated Octave file 40.11 KB Preview | Download
BIOMD0000000477.svg Auto-generated Reaction graph (SVG) 194.54 KB Preview | Download
BIOMD0000000477_urn.xml Auto-generated SBML file with URNs 115.29 KB Preview | Download
BIOMD0000000477.vcml Auto-generated VCML file 150.49 KB Preview | Download
BIOMD0000000477.pdf Auto-generated PDF file 506.51 KB Preview | Download
BIOMD0000000477.sci Auto-generated Scilab file 244.00 bytes Preview | Download

  • Model originally submitted by : Shailza Singh
  • Submitted: Aug 8, 2013 12:13:47 PM
  • Last Modified: Dec 21, 2018 5:21:27 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:21:27 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: MODEL1308080000_figure5.cps
  • Version: 2 public model Download this version
    • Submitted on: Oct 10, 2014 12:11:26 PM
    • Submitted by: Shailza Singh
    • With comment: Current version of Mol2013 - Immune Signal Transduction in Leishmaniasis
  • Version: 1 public model Download this version
    • Submitted on: Aug 8, 2013 12:13:47 PM
    • Submitted by: Shailza Singh
    • With comment: Original import of network
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(EGFR) => (PI3K)

([Epidermal growth factor receptor]) => ([Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha])
mw78df1f4c_2a96_4d8f_a009_c19ba0ec406a*mw280197c8_98de_43f0_bf01_0f332a1ab689/(mw6a74caa7_9d44_449b_854b_c1678b36ac1d+mw280197c8_98de_43f0_bf01_0f332a1ab689)

mw78df1f4c_2a96_4d8f_a009_c19ba0ec406a*[Epidermal growth factor receptor]/(mw6a74caa7_9d44_449b_854b_c1678b36ac1d+[Epidermal growth factor receptor])
mw6a74caa7_9d44_449b_854b_c1678b36ac1d=0.8 nanomole; mw78df1f4c_2a96_4d8f_a009_c19ba0ec406a=0.2 nanomole/second
(EGFR) => (Shc/Grb2/Sos1)

([Epidermal growth factor receptor]) => ([Growth factor receptor-bound protein 2; Son of sevenless homolog 2])
mw661c7759_2bd3_4c93_bb0a_823bb37b9820*mw280197c8_98de_43f0_bf01_0f332a1ab689

mw661c7759_2bd3_4c93_bb0a_823bb37b9820*[Epidermal growth factor receptor]
mw661c7759_2bd3_4c93_bb0a_823bb37b9820=0.299 1/second
(EGFR) => (JAK)

([Epidermal growth factor receptor]) => ([Tyrosine-protein kinase JAK1])
mw234b354b_eb7b_4af6_a678_9339f6b5eb8d*mw280197c8_98de_43f0_bf01_0f332a1ab689/(mw18baeb4d_ad18_4c22_95c4_2ada0f618c65+mw280197c8_98de_43f0_bf01_0f332a1ab689)

mw234b354b_eb7b_4af6_a678_9339f6b5eb8d*[Epidermal growth factor receptor]/(mw18baeb4d_ad18_4c22_95c4_2ada0f618c65+[Epidermal growth factor receptor])
mw18baeb4d_ad18_4c22_95c4_2ada0f618c65=1.8 nanomole; mw234b354b_eb7b_4af6_a678_9339f6b5eb8d=0.01 nanomole/second
(EGFR) => (PLC gamma)

([Epidermal growth factor receptor]) => ([1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; cytokine-mediated signaling pathway])
mwb3751ef8_2226_4ec3_9ac9_f92f5771a1a4*mw280197c8_98de_43f0_bf01_0f332a1ab689/(mw244e346b_4442_45db_864e_0442ceca94d1+mw280197c8_98de_43f0_bf01_0f332a1ab689)

mwb3751ef8_2226_4ec3_9ac9_f92f5771a1a4*[Epidermal growth factor receptor]/(mw244e346b_4442_45db_864e_0442ceca94d1+[Epidermal growth factor receptor])
mw244e346b_4442_45db_864e_0442ceca94d1=0.5 nanomole; mwb3751ef8_2226_4ec3_9ac9_f92f5771a1a4=2.0E-4 nanomole/second
(PLC gamma) => (PIP2)

([1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; cytokine-mediated signaling pathway]) => ([1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate])
mw18e075a4_dde4_42be_9315_e0e90d461b99*mw9a5baf6d_0285_4ad3_9499_059c553d9cf6/(mw6d4dc2a5_6fe8_4d80_93f4_b9f438b6eb0e+mw9a5baf6d_0285_4ad3_9499_059c553d9cf6)

mw18e075a4_dde4_42be_9315_e0e90d461b99*[1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; cytokine-mediated signaling pathway]/(mw6d4dc2a5_6fe8_4d80_93f4_b9f438b6eb0e+[1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; cytokine-mediated signaling pathway])
mw6d4dc2a5_6fe8_4d80_93f4_b9f438b6eb0e=1.0 nanomole; mw18e075a4_dde4_42be_9315_e0e90d461b99=0.6 nanomole/second
(DAG) => (PKC)

([diglyceride]) => ([Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3])
mw9d566811_669e_4b95_8452_c4853f54a2de*mwf20834c8_a115_460b_859c_4e3ca1ffd953

mw9d566811_669e_4b95_8452_c4853f54a2de*[diglyceride]
mw9d566811_669e_4b95_8452_c4853f54a2de=0.35 1/second
(PKC) => (IkK_NFkB)

([Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3]) => ([I-kappaB phosphorylation])
mw99befd62_975f_49e1_bfaf_22a482ce44ea*mwb4633da9_f9d6_4ad8_a7e5_da075c830e17/(mwb38e4258_82d9_4b48_8059_eccf9fd6f8e3+mwb4633da9_f9d6_4ad8_a7e5_da075c830e17)

mw99befd62_975f_49e1_bfaf_22a482ce44ea*[Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3]/(mwb38e4258_82d9_4b48_8059_eccf9fd6f8e3+[Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3])
mwb38e4258_82d9_4b48_8059_eccf9fd6f8e3=0.2 nanomole; mw99befd62_975f_49e1_bfaf_22a482ce44ea=1.2 nanomole/second
(PKC) => (Ras)

([Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3]) => ([Ras])
mwdeab2870_570e_4b2c_b73d_84c1ad8c2262*mwb4633da9_f9d6_4ad8_a7e5_da075c830e17/(mw4945db3d_e20c_4870_b96b_6fb98c4b12f6+mwb4633da9_f9d6_4ad8_a7e5_da075c830e17)

mwdeab2870_570e_4b2c_b73d_84c1ad8c2262*[Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3]/(mw4945db3d_e20c_4870_b96b_6fb98c4b12f6+[Protein kinase C alpha type; Putative serine/threonine-protein kinase-like protein CCR3])
mw4945db3d_e20c_4870_b96b_6fb98c4b12f6=1.0 nanomole; mwdeab2870_570e_4b2c_b73d_84c1ad8c2262=1.0 nanomole/second
(Shc/Grb2/Sos1) => (Ras)

([Growth factor receptor-bound protein 2; Son of sevenless homolog 2]) => ([Ras])
mw883852ed_c433_4dec_baa0_386309fc085c*mw323a57b4_8e59_4116_9ad1_fe547b89c858/(mw6069097b_159a_4bcf_a591_e496d06cf0a9+mw323a57b4_8e59_4116_9ad1_fe547b89c858)

mw883852ed_c433_4dec_baa0_386309fc085c*[Growth factor receptor-bound protein 2; Son of sevenless homolog 2]/(mw6069097b_159a_4bcf_a591_e496d06cf0a9+[Growth factor receptor-bound protein 2; Son of sevenless homolog 2])
mw883852ed_c433_4dec_baa0_386309fc085c=0.24 nanomole/second; mw6069097b_159a_4bcf_a591_e496d06cf0a9=1.2 nanomole
(Ras) => (Raf)

([Ras]) => ([RAF proto-oncogene serine/threonine-protein kinase])
mw78a1e67e_883c_497f_86a6_f85da783010e*mw173d8585_5817_4b4c_932a_cf7d673680ac/(mw5d6cf9c6_4dc0_4fe6_9afc_da397fe896b2+mw173d8585_5817_4b4c_932a_cf7d673680ac)

mw78a1e67e_883c_497f_86a6_f85da783010e*[Ras]/(mw5d6cf9c6_4dc0_4fe6_9afc_da397fe896b2+[Ras])
mw78a1e67e_883c_497f_86a6_f85da783010e=0.2 nanomole/second; mw5d6cf9c6_4dc0_4fe6_9afc_da397fe896b2=1.5 nanomole
(Ras) => (MKK4/7)

([Ras]) => ([Mitogen-activated protein kinase kinase kinase 7])
mw2f1f65d1_5633_4625_b2b7_0eb267eac293*mw173d8585_5817_4b4c_932a_cf7d673680ac/(mw0b0869f4_26bb_4d13_9124_b2c1b28e3ae1+mw173d8585_5817_4b4c_932a_cf7d673680ac)

mw2f1f65d1_5633_4625_b2b7_0eb267eac293*[Ras]/(mw0b0869f4_26bb_4d13_9124_b2c1b28e3ae1+[Ras])
mw0b0869f4_26bb_4d13_9124_b2c1b28e3ae1=1.5 nanomole; mw2f1f65d1_5633_4625_b2b7_0eb267eac293=0.4 nanomole/second
Curator's comment:
(added: 10 Sep 2013, 15:50:35, updated: 10 Sep 2013, 15:50:35)
The paper has a Flux V/s Sensitivity bar chart (figure 5) of the signalling components that are at the crosstalk points and those that show high PCA (Principal component analysis) score. Here, time-course of the fluxes of the corresponding components (components at the crosstalk points and the components that show high PCA score) of figure 5 of the papers is produced. Simulation was done using Copasi v4.10 (Build 55). The plots were generated using Gnuplot.