GENE EXPRESSION/DRUG RESISTANCE IN TRICHOMONAS

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The long term objectives of this research are to understand the basic properties that are critical for the expression of genes in the parasite Trichomonas vaginalis, to examine the role of altered gene expression in metronidazole resistant parasites and to determine the mechanism underlying drug resistance. T. vaginalis is one of the most common parasites encountered by Americans. Isolates of this parasite that are refractory to treatment with metronidazole, the only drug licensed for therapy, are frequently reported. Our previous research has provided evidence that drug resistant strains have altered transcription of genes encoding proteins that are necessary for activation of this prodrug to its cytotoxic form. Investigation of the mechanisms that govern transcription in T. vaginalis and how these mechanisms can be altered to give rise to drug resistance has lead to our discovery of a highly conserved, essential promoter element (Inr) that is necessary for transcription of all T. vaginalis protein-coding genes. We propose to define the role of this element and its interacting proteins in initiation of transcription. Possible novel mechanisms used for the translation of T. vaginalis proteins will also be examined. As our studies focus on properties of the parasite that distinguish it from its human host, the information gained may lead to identification of novel, therapeutic targets. We propose to extend our research on gene expression and drug resistance by (1) characterizing a protein that specifically binds to the essential Inr promoter element by purifying the protein and cloning the gene encoding this protein, (2) examining the role of the unusual 5' untranslated regions of mRNAs in expression of T. vaginalis genes and (3) determining whether altered gene expression is responsible for drug resistance in trichomonads. These studies will greatly enhance our understanding of gene expression in early-evolving eukaryotes. Moreover, a better understanding of the basic properties underlying gene expression in trichomonads will provide insights into the evolution of gene regulatory mechanisms in parasitic protists, as well as biochemical mechanisms that give rise to drug resistance.