Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity

View the 2014-09 Model of the Month entry for this model
  public model
Short description
Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity
This model is comprised of four models:
Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression.
The figure referring to this Crohn's Disease model is 6b.

This model is described in the article:

Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol 2014; 3: e89

Abstract:

In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014.

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.

Format
SBML (L2V4)
Related Publication
  • A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.
  • Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C
  • CPT: pharmacometrics & systems pharmacology , 0/ 2014 , Volume 3 , pages: e89
  • The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
  • In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6Rα, or the IL-6/sIL-6Rα complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6Rα complex in addition to IL-6 or IL-6Rα. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014.
Contributors
Vincent Knight-Schrijver, administrator

Metadata information

isDescribedBy
PubMed 24402116
hasTaxon
Taxonomy Homo sapiens
hasPart
Gene Ontology JAK-STAT cascade
isVersionOf
hasVersion
Human Disease Ontology Crohn's disease
isPartOf
Reactome REACT_27307.1
Curation status
Curated
Name Description Size Actions

Model files

BIOMD0000000536_url.xml SBML L2V4 representation of Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity 232.05 KB Preview | Download

Additional files

BIOMD0000000536.sci Auto-generated Scilab file 67.00 bytes Preview | Download
BIOMD0000000536.m Auto-generated Octave file 56.28 KB Preview | Download
BIOMD0000000536_urn.xml Auto-generated SBML file with URNs 229.57 KB Preview | Download
BIOMD0000000536-biopax3.owl Auto-generated BioPAX (Level 3) 185.55 KB Preview | Download
BIOMD0000000536-biopax2.owl Auto-generated BioPAX (Level 2) 108.01 KB Preview | Download
BIOMD0000000536.xpp Auto-generated XPP file 44.07 KB Preview | Download
BIOMD0000000536.vcml Auto-generated VCML file 897.00 bytes Preview | Download
BIOMD0000000536.svg Auto-generated Reaction graph (SVG) 228.75 KB Preview | Download
BIOMD0000000536.pdf Auto-generated PDF file 733.78 KB Preview | Download
Dwivedi2014_IL6_sgp130_activity_log.txt.zip Curation log.txt file summarising all changes made to original model. Includes details of figure reproduction. 1.40 KB Preview | Download
BIOMD0000000536.png Auto-generated Reaction graph (PNG) 861.66 KB Preview | Download

  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: Aug 5, 2014 1:55:21 PM
  • Last Modified: Dec 21, 2018 5:28:52 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:28:52 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Dwivedi2014_IL6_sgp130_activity_log.txt.zip
  • Version: 2 public model Download this version
    • Submitted on: Jan 13, 2017 4:04:04 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Current version of Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity
  • Version: 1 public model Download this version
    • Submitted on: Aug 5, 2014 1:55:21 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity
Curator's comment:
(added: 06 Aug 2014, 12:29:53, updated: 06 Aug 2014, 12:29:53)
Figure 6b: Suppression of CRP after 12 weeks of sgp130Fc administration. Separate curves represent timing between doses. sgp130Fc is an antibody modified with sgp130, an endogenous Inhibitor and sequestration glycoprotein of the IL6/IL6Ra soluble complex. Three separate simulations, one for each dose regimen, were carried out by parameter scan for Dose with 8 intervals between 0 and 2000 mg. Results plotted in libreCalc.