Computational modelling of steroid hormone biosynthesis and metabolism

Louw, Carla (2020-03)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: This study describes the use of computational modelling and statistical techniques to address three topics in the field of steroid hormone research. The first is the hypocortisolism seen in the South African Angora goat. In a comparative analysis the construction, parameterisation and validation of a model describing the D4 and D5 pathways in both the ovine and Angora goat species are completed. With these models the issue of identifying a possible treatment target is addressed. The second topic is the steroidogenic activity in the human liver. This includes the construction, parameterisation and validation of a model describing the relative conversion of classic androgens and 11-oxygenated androgens to their respective 5a or 5b reduction products in the human liver. The model indicates that under physiological steady state conditions the 5b reduction of both the classic androgens and the 11-oxygenated androgens are the preferred reaction. The third and final topic discussed in this study is the steroidogenic activity in prostate cancer C42B cells. The construction, parameterisation and validation of a model describing the steroid hormone biosynthesis in the C42B castration resistant prostate cancer cell line is included. Three possible treatment targets for castration resistant prostate cancer in C42B cells are identified. This study also describes the development of an add-on Mathematica package, IdentifiabilityAnalysis, which simplifies the process of model parameterisation and identifiability analysis. This package is used throughout this study.

AFRIKAANSE OPSOMMING: Hierdie studie beskryf die gebruik van wiskundige modellering en statistiese tegnieke om drie onderwerpe op die veld van steroïedhormoon navorsing aan te spreek. Die eerste is die hipokortisolisme wat in die Suid-Afrikaanse Angorabok gesien word. In ’n vergelykende analise is die konstruksie, parameterisering en validering van ’n model wat die D4 and D5 padweë beskryf, beide in die skaap- en Angorabokspesies voltooi. Met hierdie modelle word die kwessie van die identifisering van ’n moontlike teiken vir behandeling aangespreek. Die tweede onderwerp is die steroïdogeniese aktiwiteit in die lewer van die mens. Dit sluit in die konstruksie, parameterisering en validering van ’n model wat die relatiewe omskakeling van klassieke androgene en 11-geöksideerde androgene na hul onderskeie 5a of 5b reduksieprodukte in die menslike lewer beskryf. Die model dui aan dat die 5b reduksie van beide die klassieke androgene en die 11- geöksideerde androgene by fisiologiese bestendige toestand die voorkeurreaksie is. Die derde en laaste onderwerp wat in hierdie studie bespreek word, is die steroïdogeniese aktiwiteit in prostaatkanker C42B-selle. Die konstruksie, parameterisering en validering van ’n model wat die biosintese van die steroïedhormone in die C42B-kastrasie-weerstandige prostaatkanker-sellyn beskryf, is ingesluit. Drie moontlike teikens vir die behandeling van kastrasie-weerstandige prostaatkanker in C42B-selle word geïdentifiseer. Hierdie studie beskryf ook die ontwikkeling van ’n addisionele Mathematica-pakket, IdentifiabilityAnalysis, wat die proses van modelparameterisering en identifiseerbaarheidsanalise vergemaklik.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/108360
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