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

这项建议的目的是研究一种或多种机制 克氏锥虫维持钙稳态的机制不同 阶段，以及这些进程可以通过什么方式中断 现有和潜在的杀锥虫药物。这些研究的目标是 为寻找新的机遇作出贡献 抗寄生虫化疗。线粒体钙离子的作用机制 转运，钙离子参与细胞外信号的调节 寄生虫的线粒体内代谢及其分子生物学研究 杀锥虫药物(β-拉帕酮、硝呋莫司、苯硝唑、 和龙胆紫)对线粒体Ca~(2+)转运将是一个区域 因为我们证明了这一点，而不是之前的 报告表明，钙离子转运系统仅在 脊椎动物组织中的线粒体、克氏锥虫上胚体和 无鞭毛体也有类似的系统。的第二部分。 提案将包括调查胞浆的调节 寄生虫体内Ca~(2+)浓度及Ca~(2+)在其中的作用 对宿主细胞的入侵。血浆中钙泵的存在 膜、内质网、核和其他细胞器， 钙调素在这些钙泵上的作用和肌醇磷酸酶的作用 在内质网钙释放中，内质网钙离子的变化 侵袭过程中细胞内钙离子的变化及存在的影响 (硝呋莫司、苯硝唑、龙胆紫)和潜在的杀锥虫药 药物(产生氧化应激的药物、钙拮抗剂和钙 通道阻滞剂)对这些寄生虫钙动态平衡的影响 调查过了。由于几种现有的和潜在的杀锥虫剂 似乎起到了钙拮抗剂的作用或扰乱了其他 这些研究将阐明钙离子在生物系统中的作用 寄生虫新陈代谢和这些药物作为杀锥虫药物的重要性 探员们。

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.