Research
The human pathogenic parasites Trypanosoma brucei and Trypanosoma cruzi exhibit unique metabolic features and pose a huge global burden on health and economic development. Powerful forward and reverse genetics methods, and whole-genome sequence information, facilitate studies of the basic parasite biology and potential drug targets. We study the “editosome”, a remarkable molecular machine in RNA biology, and participate in a multi-lab effort toward drug development against pathogenic trypanosomes. Our studies examine parasite life-cycle forms that infect the bloodstream and the insect vector of transmission.
RNA biology in trypanosomes
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The editosome is a large molecular machine that remodels the mitochondrial transcriptome through uridylate-specific indels. This process creates functional protein-coding sequences in primary mRNAs packed with stop codons. Trypanosomes diverged from other eukaryotic lineages over 100 Ma, however, RNA editing, RNA interference, CRISPR, and mRNA splicing exhibit mechanistic analogies including the use of non-coding guide RNAs. Our long-term goal is to dissect the editosome regulatory mechanisms during the life stages of T. brucei. We currently study the organization and dynamic interaction of components in the editing apparatus, including an RNA helicase motor identified in our lab. These studies include an array of approaches including protein and RNA structure, genomics, bioinformatics, and proteomics.
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Development of lead compounds against trypanosomes
T. brucei and T. cruzi are the causative agents of critical human diseases, including African Sleeping Sickness and American Chagas Disease, respectively. We have an exciting collaboration with Tom Meek’s lab that proposes to develop lead drugs with selective inhibitory activity against essential proteins (targets) in pathogenic trypanosomes. We are testing drugs developed in the Meek lab against essential N-ribosyl transferases and cysteine proteases, including cruzain, rhodesain, and TbCatB. We use CRISPR gene editing, and gene knockouts among other molecular tools to manipulate the expression of protein targets, validate their essentiality in transgenic parasites, and establish on-target specificity by candidate inhibitors.
