Dynamical modelling of the effect of insulin-like growth factor 1 on human cell growth : a thesis presented in fulfilment of the requirements for the degree of Master of Science in Mathematics at Massey University, Albany, New Zealand
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Date
2013
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Massey University
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Abstract
Insulin-like Growth Factor-1 (IGF-1) plays a vital role in human growth and development. Interactions with IGF-1 receptors and IGF-1 binding proteins (IGFBPs) regulate
IGF-1 function. Boroujerdi et al. (1997) published a mathematical model describing dynamic regulation of IGF-1. We extended the Boroujerdi et al. (1997) model to evaluate
the role of cyclic Gly-Pro (CGP) in dynamic regulation of IGF-1 function. Recent research from the Liggins Institute suggests that a metabolite of IGF-1, CGP, may have a
role in regulating IGF-1 homeostasis, possibly through competitive binding to IGFBPs.
The goal of the research was to understand the kinetics of IGF-1, IGFBPs and CGP,
along with their interactions with IGF-1 receptors. This goal and an understanding
of how the kinetics mediate IGF-1 function was achieved through consideration of the
nonlinear dynamics of the physiology using a modelling approach.
The resulting models were directly focused on three central theories. The first is that
CGP can either inhibit, stimulate or maintain IGF-1 function based on the extent of receptor binding. The other theories are that CGP regulates IGF-1 through competitive
binding to IGFBPs and that CGP does not directly interact with the IGF-1 receptors.
Four in vitro models were developed and fitted to experimental data. These included
two implicit models which relied on two feedback terms in the equations. The second
model was an alteration of the first to produce a reduction in cell number levels for high
doses of CGP added to the system. The other two models were explicit models, the
first of which could not express the IGF-1 dynamics well (it showed no CGP response).
Although the models incorporated these theories, there are other mechanisms influencing the system which will have an effect on the data. Therefore the fourth model
was introduced as a simplified version of the third. This was aimed at resembling cell
culture situations more closely and was designed to have the receptor bound IGF-1
dependent on IGF-1 and CGP production rates.
The models can be used to predict cellular response in an in vitro situation, or as
a basis for further research in this field.
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Keywords
Insulin-like growth factor-binding proteins, Growth factors, Human cell growth, Cells