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

本提案的目的是研究一种或多种机制， 在克氏锥虫中维持Ca 2+稳态的机制 阶段，以及这些过程可能被破坏的方式 现有的和潜在的杀锥虫药物。 这些研究的目的是 协助确定新的机会， 抗寄生虫化疗 线粒体Ca ~（2+）的作用机制 运输，Ca 2+的参与，在调节 寄生虫线粒体内代谢的研究 杀锥虫药物（β-拉帕酮，硝呋莫司，苄硝唑， 和龙胆紫）对线粒体Ca 2+转运的影响将是一个领域 因为我们证明了，与以前相比， 报告表明，Ca 2+运输系统只发生在 脊椎动物组织中的线粒体，T.克氏上鞭毛体和 无鞭毛体也有类似的系统。 的第二部分 该提案将包括研究细胞质的调节， 寄生虫体内Ca ~（2+）浓度及其作用 入侵宿主细胞。 血浆中存在Ca 2+泵 膜、内质网、细胞核和其他细胞器， 钙调素对这些钙泵的作用，磷酸肌醇的作用 在内质网释放Ca 2+方面， 细胞内Ca 2+在入侵过程中，和现有的影响， （硝呋莫司、苄硝哒唑、龙胆紫）和潜在的杀锥虫剂 药物（产生氧化应激的药物、钙拮抗剂和钙拮抗剂） 通道阻滞剂）对这些寄生虫的Ca 2+稳态的影响将是 研究了 由于几种现有的和潜在的杀锥虫剂 似乎作为Ca 2+拮抗剂或干扰Ca 2+稳态在其他 生物系统，这些研究将阐明钙的作用， 寄生虫代谢和这些药物作为杀锥虫药的重要性 剂.

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.