Investigations of signaling pathways and their potential benefits in combating trypanosomatid diseases
Keller, Sharon King
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Trypanosomes are protist parasites, belonging to the order Kinetoplastida, characterized by the presence of a kinetoplast, a DNA-containing structure within the single mitochondrion of the parasite. This group is of great importance to the health of humans and domestic animals and has been the subject of much research. Signaling pathway such as the ones examined in this dissertation have been extensively studied in mammalian systems bringing to light knowledge that could be applied to elucidating the role of these pathways in these parasites. The extensive studies of the inositol 1, 4, 5-trisphosphate/diacylglycerol (IP3/DAG) pathway in mammals and its implication in essential cellular process such as growth, differentiation, metabolism, among others, ignited interest in exploring the role of this pathway in the biology of the parasite. Targeting this pathway could render a way to disrupt the life cycle of the parasite. Our work on Trypanosoma brucei phosphatidylinositol phospholipase C demonstrates that this pathway is active in the parasites and could be involved in growth and infectivity. T. brucei has genetic tools that make it model system for exploring the effects of all parts of this pathway. Phosphodiesterase inhibitors have had success in targeting certain PDE families in humans. The parasite PDEC of Trypanosoma cruzi has structural similarity with human PDE4B, but we were able to screen compounds that caused inhibitory effects, both in vitro and in vivo, selectively targeting the parasite PDE. This work demonstrated a role for PDEs in growth and in response to osmotic stress in parasites illustrating that even though the host and parasite PDEs are similar, the parasite enzyme can be selectively inhibited. The results from the compound testing allowed for the construction of a model that can be used to guide lead compound optimization and drug discovery. Our focus on both pathways have elucidated some fascinating similarities as well as differences compared to what is known from mammalian studies providing new insights in to the role of signaling in Trypanosomes.