Developmental regulation of mitochondrial RNA editing in trypanosomes

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Trypanosomatid species are related parasitic unicellular organisms that are responsible for serious human diseases such as African sleeping sickness, Chagas' disease, and leishmaniasis. Trypanosoma brucei for instance is a bloodstream, extracellular pathogen that affects the central nervous system and causes human sleeping sickness. T. brucei mortality rate alone is 48,000 individuals per year and has an annual loss of 1.5 million disability-adjusted life years (DALYs). These diseases have also been introduced to the western world by blood transfusion and organ donation of immigrants and returning soldiers. The survival of this vector-borne parasite through its intricate life cycle is extensively dependent on the fine regulation of hundreds of genes. This includes, differential expression of their mitochondrial genes, representing a highly diverged system from those of mammals (hosts) or other metazoan and protozoan organisms. We hypothesize that understanding the regulation of gene expression in these lethal pathogens is essential to understanding their biology and identification of key regulatory modules (likely drug targets) that may be shared in multiple trypanosomatid pathogens. In the short term, this research will identify and characterize the essential factors (regulators) responsible for differential mechanisms of ATP generation during the life-stages of T. brucei. For this purpose, we will use our computational tools along with experimental approaches to identify factors that modulate the events during transition. The long term goal of this research is to provide a global map of the molecular network that regulates the energy production. As this network plays indispensable roles in transmission, infectivity and disease, this project will pave the way for much needed future therapeutics against trypanosomatids.**