| My doctoral studies focused on the fatty acid metabolism of the deadly protozoan parasite, Trypanosoma brucei. Fatty acid metabolism in T. brucei can be broadly divided into two pathways, synthesis and uptake. In Chapters 2-4 I describe experiments investigating the parasite's fatty acid synthesis pathway. Chapter 2 contains the initial characterization of acetyl-CoA carboxylase (ACC) in T. brucei. Knockdown of TbACC by RNA interference (RNAi) reduced parasite virulence in a mouse model, suggesting that TbACC has the potential to be utilized as a drug target. Chapters 3 and 4 explore the effects of two known ACC inhibitors, the aryloxyphenoxypropionate herbicide, haloxyfop and the green tea catechin, (--)-epigallocatechin-3-gallate (EGCG) on TbACC activity and parasite growth. Both compounds inhibited TbACC enzymatic activity and parasite growth in vitro. In Chapters 5 and 6 contain research that utilizes forward and reverse-genetic techniques to study T. brucei fatty acid uptake. In Chapter 5 I begin to characterize the role of the parasite's acyl-CoA synthetase genes in fatty acid uptake and growth. Further, I demonstrate that fatty acid uptake is in part a protein mediated process. Chapter 6 describes an RNAi screen for genes involved in T. brucei fatty acid uptake. Together these studies build upon our knowledge of the unique fatty acid metabolism of T. brucei, bringing us one step closer to a potential cure for this horrible disease. |
