Computational Model of GCSF Endocytic Trafficking Dynamics
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
Version 02 was created from Version 01 on 30/04/07 by James Lawson. The variable N was defined using an equation from the Sarkar and Lauffenburger 2003 paper. Version 03 was created from Version 02 by James Lawson on 01/05/07 and now includes the pharmacological simulations described in the paper. This file is known to read in PCEnv.
Model Structure
Currently, drug design and development takes, on average, 12 years and costs more than 800 million US dollars. Much of this time and money is spent on experiments and drugs that fail. There is very little mechanistic understanding as to how the various levels of biological complexity - from molecular interactions, to cellular function, to tissue organisation, to whole organs and beyond - are integrated. Hierarchical mathematical models provide a method for integrating this data. Specifically, in the model described here, Sarkar and Lauffenburger focus on the case of granulocyte colony-stimulating factor (GCSF).
GCSF is of great clinical importance, especially for cancer patients undergoing chemotherapy. The drug is injected into the blood stream where it then diffuses to the bone marrow and binds to its receptor GCSFR on precursor cells, inducing them to replicate and differentiate into mature neutrophils. In this way, the neutrophil count of immunocompromised patients is significantly increased. However, the bone marrow precursor cells engulf and degrade the GCSF, a negative feedback mechanism that reduces its potency. In addition, mature bone cells express the receptor GCSFR, and they bind, engulf and degrade the drug from the bloodstream. Thus, there is a significant negative feedback loop that reduces the lifetime of the drug.
The mathematical model developed by Sarkar and Lauffenburger relates extracellular GCSF depletion to the molecular properties of the ligand and the cells expressing the GCSF receptor (see the figure below). The authors then further integrated this cell-level model into a physiologically relevant pharmacokinetic/pharmacodynamic model.
The model has been described here in CellML (the raw CellML description of the Sarkar and Lauffenburger 2003 model can be downloaded in various formats as described in ).
The complete original paper reference is cited below:
Cell-Level Pharmacokinetic Model of Granulocyte Colony-Stimulating Factor: Implications for Ligand Lifetime and Potency in Vivo, Casim A. Sarkar and Douglas A. Lauffenburger, 2003,
Molecular Pharmacology
, 63, 147-158. (Full text (HTML) and PDF versions of the article are available on the Molecular Pharmacology website.) PubMed ID: 12488547
reaction diagram
Cell-level trafficking model for the GCSF/GCSFR system.
Rs
cell surface receptor
$\frac{d \mathrm{Rs}}{d \mathrm{time}}=(\mathrm{kr}\mathrm{Cs}+\mathrm{Vs}-\mathrm{kf}L\mathrm{Rs}+\mathrm{keR}\mathrm{Rs})N$
Cs
cell surface complex
$\frac{d \mathrm{Cs}}{d \mathrm{time}}=-(\mathrm{kf}L\mathrm{Cs}+\mathrm{kr}\mathrm{Cs}+\mathrm{keC}\mathrm{Cs})N$
Li
intracellular ligand
$\frac{d \mathrm{Li}}{d \mathrm{time}}=((\mathrm{kri}\mathrm{Ci}-\mathrm{kfi}\mathrm{Li}\mathrm{Ri})\frac{1.0}{\mathrm{NA}\mathrm{Ve}}-\mathrm{krec}\mathrm{Li})N$
Ri
intracellular receptor
$\frac{d \mathrm{Ri}}{d \mathrm{time}}=(\mathrm{kri}\mathrm{Ci}+\mathrm{keR}\mathrm{Rs}-\mathrm{kfi}\mathrm{Li}\mathrm{Ri}+\mathrm{kdeg}\mathrm{Ri})N$
Ci
intracellular complex
$\frac{d \mathrm{Ci}}{d \mathrm{time}}=(\mathrm{kfi}\mathrm{Li}\mathrm{Ri}+\mathrm{keC}\mathrm{Cs}-\mathrm{kri}\mathrm{Ci}+\mathrm{kdeg}\mathrm{Rs})N$
L
extracellular ligand
$\frac{d L}{d \mathrm{time}}=(\mathrm{krec}\mathrm{Li}\mathrm{Ve}\mathrm{NA}+\mathrm{kr}\mathrm{Cs}-\mathrm{kf}L\mathrm{Rs})\frac{N}{\mathrm{NA}}-\mathrm{kl\_WT}L$
Ld
degraded ligand
$\frac{d \mathrm{Ld}}{d \mathrm{time}}=\mathrm{kdeg}\mathrm{Ci}N$
$n=N$
$\frac{d n}{d \mathrm{time}}=\mathrm{Kin}(1+\frac{\mathrm{emax}\left(\frac{L\mathrm{kdiwt}}{\mathrm{kd}}\right)^{\mathrm{gamma}}}{\mathrm{ec50}^{\mathrm{gamma}}+\left(\frac{L\mathrm{kdiwt}}{\mathrm{kd}}\right)^{\mathrm{gamma}}})-\mathrm{kout}n$
$\frac{d \mathrm{L4}}{d \mathrm{time}}=\frac{Q}{\mathrm{V4}}(L-\mathrm{L4})\frac{d \mathrm{n1}}{d \mathrm{time}}=\mathrm{k13}\mathrm{n1}\frac{d \mathrm{n2}}{d \mathrm{time}}=\mathrm{k23}\mathrm{n2}$
10
100000
0.001
Casim
Sarkar
A
Molecular Pharmacology
James
Lawson
R.
12488547
Douglas
Lauffenburger
A
j.lawson@auckland.ac.nz
2003-01-01
Douglas
Lauffenburger
A
2007-05-01
Sarkar and Lauffenburger's 2003 computational model of GCSF endocytic
trafficking dynamics.
neutrophil
keyword
pharmacology
signal transduction
gscf
gpcr
pharmacokinetics
neutrophil
Cell-Level Pharmacokinetic Model of Granulocyte Colony-Stimulating Factor: Implications for Ligand Lifetime and Potency in Vivo
63
147
158
Casim
Sarkar
A
The University of Auckland, Bioengineering Institute
Catherine Lloyd
This is the CellML description of Sarkar and Lauffenburger's 2003 computational model of GCSF endocytic trafficking dynamics. The pharmacokinetic and pharmacodynamic part of the model is now included in version 03.
University of Auckland
Bioengineering Institute