Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity

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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.

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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

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
  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: Aug 5, 2014 1:55:21 PM
  • Last Modified: Jan 13, 2017 4:04:04 PM
Revisions
  • 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.