Mathematical modelling of hypoglycaemia and lactic acidosis in the bloodstream of Plasmodium berghei infected rats: a feasibility study
Date
2016-03
Authors
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Journal ISSN
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Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT : Needless prescription and overuse of anti-microbial compounds served as a catalyst
for the evolution and rise of multiple drug resistant pathogens, one of humanities
greatest threats in the anti-biotic era. Resistance to our last line of defence drugs
for malaria, a disease that reportedly caused the deaths of more than half a million
people in 2013, is being reported in South-east Asia, necessitating the need for a
novel high throughput method of anti-malarial drug development. Advances in the
field of systems biology and further development of metabolic control analysis, could
be used to identify drug targets from metabolic models.
The purpose of this project was to investigate the feasibility of creating a whole
body model of rats infected with P. berghei. To assess the feasibility, a initiatory glycolytic
model was constructed and the possibility of modelling the change in blood
parameters over the course of a malarial infection was investigated. Wistar rats were
infecting with P. berghei, ANKA strain, and blood parameters, including blood glucose
and lactate concentration, haematocrit and parasitemia was measured and the
relationship between the parameters evaluated. Furthermore, pulse experiments
were performed to analyse the possibility of modelling the homeostatic potential of
the rat. Microscopy and enzymatic glucose and lactate concentration determinations
proved to be reliable and accurate methods to measure blood parameters. In
addition, a relationship between parasitemia and the other blood parameters could
be quantified, providing evidence that the physiological changes during malarial infection
could be modelled. The glycolytic enzymes were liberated from the parasites
and biochemically characterized. The kinetic parameters obtained from the characterization
were subsequently used to construct a glycolytic model. Steady state
concentrations predicted by the preliminary model fall within physiological ranges, indicating that the model construction is feasible.
In conclusion, the results from the experiments, biochemical characterization of
the glycolytic enzymes isolated from P. berghei and preliminary model construction
of the glycolytic pathway supports the feasibility of creating a complete whole body
model, warranting further investigation.
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Description
Thesis (MSc)--Stellenbosch University, 2016
Keywords
Glycolysis, Enzyme kinetics -- Mathematical modelling, Plasmodium berghei (P. berghei), UCTD, Rats -- Metabolism, Malaria -- Treatment, Parasitology -- Research