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

杀锥虫药物的作用方式——CA 的参与

• 批准号: 2062105
• 负责人: ROBERTO DOCAMPO
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2062105
• 关键词: Trypanosoma cruzi; affinity chromatography; antiprotozoal agents; calcium channel; calcium channel blockers; calcium flux; calcium transporting ATPase; calmodulin; cell membrane; drug screening /evaluation; endoplasmic reticulum; enzyme activity; enzyme inhibitors; fluorescence microscopy; host organism interaction; intracellular parasitism; ion transport; laboratory mouse; laboratory rat; life cycle; mitochondrial membrane; trypanosomiasis

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.

该提案的目的是研究一个或多个机制 克氏锥虫通过何种方式维持 Ca2+ 稳态 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。 这些研究的目标是 为寻找新的机会做出贡献 抗寄生虫化疗。 线粒体Ca2+的机制 运输，Ca2+参与调节 寄生虫的线粒体内代谢及其研究 杀锥虫药物（β-拉帕酮、硝呋莫司、苯硝唑、 和龙胆紫）对线粒体 Ca2+ 运输将是一个区域 自从我们证明，与之前相比，集中度 报告表明 Ca2+ 运输系统仅发生在 来自脊椎动物组织、T. cruzi 上鞭毛体的线粒体和 无鞭毛体也具有类似的系统。 第二部分 该提案将包括调查细胞质的调节 寄生虫的 Ca2+ 浓度以及 Ca2+ 在寄生虫中的作用 入侵宿主细胞。 血浆中存在 Ca2+ 泵 膜、内质网、细胞核和其他细胞器 钙调蛋白对这些 Ca2+ 泵的作用，磷酸肌醇的作用 内质网释放 Ca2+ 的变化 侵袭过程中细胞内的Ca2+，以及现有的影响 （硝呋莫司、苯硝唑、龙胆紫）和潜在的杀锥虫作用 药物（产生氧化应激的药物、Ca2+拮抗剂和钙 通道阻滞剂）对这些寄生虫的 Ca2+ 稳态的影响 调查了。 由于几种现有的和潜在的杀锥虫剂 似乎在其他方面充当 Ca2+ 拮抗剂或扰乱 Ca2+ 稳态 生物系统中，这些研究将阐明 Ca2+ 在 寄生虫代谢以及这些药物作为杀锥虫剂的重要性 代理。