Modular control analysis and its application to glucose metabolism in plasmodium falciparum-infected erythrocytes

Fisher, Joel Chanse (2021-12)

Thesis (MSc)--Stellenbosch University, 2021.

Thesis

ENGLISH ABSTRACT: Disease treatment is achieved through the administration of medication acting at the molecular level which results in changes at the physiological level. These changes are caused by molecular interactions which are usually complex and not well understood. Research often focuses on the mechanism of action of the drug as well as the specificity and binding affinity for the drug target. Such research is important, however, understanding and analysing the drug effects at the physiological level are equally important. The analysis and quantification of these effects can be difficult in large, complex systems. Consequently, such systems are mostly analysed from a broad perspective, often with the implementation of computational techniques including mathematical modelling. Analyses can then be performed using specialised mathematical frameworks, such as modular control analysis. These frameworks often focus on determining the control of groups of reactions (modules) and are usually complex, requiring detailed knowledge of the framework prior to implementation. To this end, modular control analysis was formulated in Mathematica and a software package was constructed to automate the application of the analysis framework. Use of the package was demonstrated on a model of glucose metabolism in Plasmodium falciparum- infected erythrocytes. The control of the whole parasite was determined, with the control of the parasite on the flux through itself and the infected erythrocyte determined to be near complete. Use of the package to analyse models with multiple modules was also demonstrated. In this way, use of the modular control analysis framework has been simplified, with only fundamental knowledge required to perform analyses with the software package.

AFRIKAANSE OPSOMMING: Siektes word behandel deur die toediening van medikasie wat op molekulêre vlak werk en veranderinge op _siologiese vlak tot gevolg het. Hierdie veranderinge word veroorsaak deur molekulêre interaksies wat gewoonlik kompleks is en nie goed verstaan word nie. Navorsing fokus dikwels op die werkingsmeganisme van die geneesmiddel sowel as die spesi_siteit en bindingsa_niteit vir die geneesmiddelteiken. Sulke navorsing is belangrik, maar om die geneesmiddele _ekte op _siologiese vlak te verstaanen te ontleed is ewe belangrik. Die ontleding en kwanti_sering van hierdie e_ekte kan moeilik wees in groot, komplekse stelsels. Gevolglik word sulke stelsels meestal vanuit 'n breë perspektief ontleed, dikwels deur die implementering van berekeningstegnieke, insluitend wiskundige modellering. Ontledings kan dan uitgevoer word met behulp van gespesialiseerde wiskundige raamwerke, soos modulêre kontrole-analise. Hierdie raamwerke fokus dikwels op die bepaling van die beheer van groepe reaksies (modules) en is gewoonlik kompleks, wat gedetailleerde kennis van die raamwerk vereis voor implementering. Vir hierdie doel is modulêre kontrole-analise in Mathematica geformuleer en 'n sagtewarepakket is saamgestel om die toepassing van die ontledingsraamwerk te outomatiseer. Gebruik van die pakket is gedemonstreer op 'n model van glukosemetabolisme in Plasmodium falcipa- rum-geïnfekteerde rooibloedselle. Die beheer van die hele parasiet is bepaal, en dit is gevind dat die parasiet byna volledig beheer op die _uksie deur homself en die besmette rooibloedsel het. Die gebruik van die pakket om modelle met veelvuldige modules te ontleed is ook gedemonstreer. Op hierdie manier is die gebruik van die modulêre kontrole-analise raamwerk vereenvoudig, met slegs fundamentele kennis wat nodig is om ontledings met die sagtewarepakket uit te voer.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/124259
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