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Investigating the function of CLK1 kinase in Trypanosoma brucei and identifying other essential kinases


The work presented in this thesis was motivated primarily by trying to explore the potential of protein kinases as therapeutic targets for the treatment of HAT. The first part of the thesis was aimed at identifying novel protein kinase targets in T. brucei by conducting a high-throughput RNAi screen against a subset of the T. brucei kinome. This study validated our luciferase-based assay method as a suitable assay for high-throughput RNAi screens in T. brucei. More importantly, it identified two kinases, CRK12 and ERK8, that are essential for normal proliferation by the parasite, presenting new therapeutic avenues warranting further exploration. The second part of the thesis work was aimed at investigating the function of a previously identified essential kinase, TbCLK1. This work was motivated by the fact that information relating to a potential drug target can aid in the drug discovery process by providing valuable phenotypic readouts for inhibition studies, but also by helping to identify downstream substrates that may themselves become drug targets. In this work, evidence is presented that strongly suggests TbCLK1 is essential for cis-splicing in T. brucei and that it may potentially be involved in other functions.

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