Research Description

Modeling Plasmodium falciparum

In Africa alone, malaria claims the life of a child every 30 seconds. The advent of drug resistant strains of Plasmodium has increased the severity of the disease, which will claim further lives unless novel anti-malarials are discovered. Since Plasmodium is entirely dependent on glycolysis for energy, several glycolytic enzymes have been proposed as drug targets. To analyze the pathway as a whole we have constructed a kinetic model of glycolysis for the asexual Plasmodium falciparum, using experimentally determined enzyme properties, which was validated with flux measurements in intact parasites and with inhibitor titrations. The model is being extended to whole body glucose metabolism in malaria patients.

Hierarchical modelling of disease states at whole body level

Drugs usually have a very specific target, often affecting a single chemical reaction, while disease states manifest themselves at the whole body level. To evaluate the effect of inhibiting a single reaction at the whole body level a multi-level or hierarchical approach is necessary. We are developing a mathematical modelling framework to simulate drug effects at a whole body level. The framework is generic but is being tested on whole body glucose metabolism in malaria patients.

Data and model management.

In 2001 we started the JWS Online model database and simulator, and since then we have actively maintained and improved the simulation services and database content. The model database containes curated mathematical models for biological systems that have been published in the scientific literature. We collaborate in model exchange with the EBI hosted Biomodels database and are involved in large European Systems Biology initiatives for data and model management. The most current initiative is FAIRDOM in the ERASysApp initiative for which JWS Online is the model simulation tool that is integrated in the SEEK platform.

Cholesterol metabolism in Mycobacterium tuberculosis

M. tuberculosis, the bacterium responsible for TB, can grow on cholesterol as the main carbon and energy source, using a metabolic pathway with many reaction steps and enzymes that are not found in the human host. We started a combined experimental and modelling project to analyse the flux control distribution in the pathway as an initial step to identify potential drug target to combat this important human pathogen. This is a collaborative project where the experimental work with M. tuberculosis will be performed in the group of Prof V. Mizrahi at UCT and the modeling and enzymological studies will be performed at Stellenbosch University.

Insulin signaling in muscle cells

In a project to ultimately study type 2 diabetes, we have started with the construction and validation of mathematical models for the insulin signaling pathway and its link to glucose uptake and metabolism in muscle cells. This is combined experimental and modelling project in collaboration with the group of Prof K. Myburg in the Department of Physiology at Stellenbosch University for the cell culturing work.

HIV pathogenesis and epidemiology

In this project we aim to first get an overview of the existing mathematical models for HIV pathogenesis at the person level, and for the epidemiology at the population level. On the basis of this overview an assesment will be made whether more mechanistic models, in contrast to the traditionally used phenomenological models can increase the predicitve power of these models.