MODE OF ACTION TRYPANOCIDAL DRUGS--INVOLVEMENT OF CA++

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The objectives of this proposal are to study the mechanism or mechanisms by which Ca2+ homeostasis is maintained in Trypanosoma cruzi different stages, and the ways by which these processes can be disrupted by existing and potential trypanocidal drugs. The goal of these studies is to contribute to the identification of new opportunities for antiparasitic chemotherapy. The mechanism of mitochondrial Ca2+ transport, the involvement of Ca2+ in the regulation of the intramitochondrial metabolism of the parasites and the study of the effect of trypanocidal drugs (beta-lapachone, nifurtimox, benznidazole, and gentian violet) on the mitochondrial Ca2+ transport will be one area of concentration since we demonstrated that, in contrast to previous reports indicating that a Ca2+ transport system occurs only in mitochondria from vertebrate tissues, T. cruzi epimastigotes and amastigotes also possess a similar system. The second portion of the proposal will consist of investigating the regulation of the cytosolic Ca2+ concentration of the parasites and the role of Ca2+ in parasite invasion of the host cells. The presence of Ca2+ pumps in the plasma membrane, endoplasmic reticulum, nucleus, and other organelles, the action of calmodulin on these Ca2+ pumps, the role of inositol phosphates in Ca2+ release from the endoplasmic reticulum, the changes in intracellular Ca2+ during invasion, and the effect of existing (nifurtimox, benznidazole, gentian violet), and potential trypanocidal drugs (drugs that produce oxidative stress, Ca2+ antagonists, and calcium channel blockers) on Ca2+ homeostasis of these parasites will be investigated. Since several existing and potential trypanocidal agents appear to act as Ca2+ antagonists or perturbing Ca2+ homeostasis in other biological systems, these studies will clarify the role of Ca2+ in parasite metabolism and the importance of these drugs as trypanocidal agents.