ORGANELLE GENOMES OF MALARIAL PARASITES

该项目的长期目标是了解线粒体 疟疾寄生虫的遗传系统，以评估线粒体生理学， 并评估线粒体对抗疟疾药物的反应。 期间 在过去的几年里，疟疾寄生虫--事实上， 所有的顶复门动物都含有两个非常不寻常的细胞质基因组：一个是6- 在这个实验室里发现的一个kb的DNA元件，似乎是 线粒体基因组，另一个是35 kb的环状DNA， 被认为是线粒体DNA，现在被认为是质体 具有未知函数的导数。 这些基因组代表了 不寻常的遗传系统，并驻留在细胞器，被证明或 抗疟药物行动的潜在地点。 越来越明显的是 除了氧化磷酸化，线粒体也起着关键作用， 在大多数真核生物的许多代谢步骤中起作用。 干扰 这些功能对这些生物体的生存是有害的。 的 该项目的中心假设是，线粒体功能的sin 疟疾寄生虫也不例外。 然而，缺乏适当的 工具和试剂阻碍了这一长期被忽视领域的进展。 在开发了某些新方法和试剂后，该实验室 建议将其应用于推进对线粒体的深入了解， 疟疾寄生虫 抗疟疾化合物的作用， 羟基萘醌类和8-氨基喹啉类对线粒体电子 恶性疟原虫和约氏疟原虫的运输将通过 监测膜电位和呼吸。 分子机制 将调查对这些药物的潜在耐药性。 变化 线粒体功能伴随着性分化。 将研究恶性疟原虫。 不寻常的特点转录和 在寄生虫线粒体中的翻译--产生大量的转录物， 反式相关嵌合核糖体的可能性-将被分析， 了解可能揭示其他目标的潜在机制 用于抗疟疾药物的作用。

Long term objectives of this project have been to understand mitochondrial genetic system of malarial parasites, to assess mitochondrial physiology, and to assess mitochondrial responses to antimalarial drugs. During the past few years, it has become apparent that malarial parasites -- indeed, all apicomplexans --contain two very unusual cytoplasmic genomes: one, a 6- kb DNA element, discovered in this laboratory, that appears to be the mitochondrial genome, and the other, a 35-kb circular DNA, previously thought to be the mitochondrial DNA, now believed to be a plastid derivative with as yet unknown functions. These genomes represent very unusual genetic systems, and reside in organelles that are proven or potential sites for antimalarial drug actions. It is increasingly apparent that, besides oxidative phosphorylaiton, mitochondria also play critical roles in numerous metabolic steps in most eukaryotes. Interference with these functions is detrimental to the survival of these organisms. The central hypothesis of this project is that mitochondrial function sin malarial parasites are no exception to this. Yet, lack of appropriate tools and reagents has hampered progress in this long-neglected area. Having developed certain new approaches and reagents, this laboratory proposes to apply them to advance athe understanding of mitochondria in malarial parasites. Effects of antimalarial compounds such as hydroxynaphthoquinones and 8-aminoquinolines on mitochondrial electron transport in Plasmodium falciparum and P. yoelii will be examined by monitoring membrane electropotential and respiration. Molecular mechanisms underlying resistance to these drugs will be investigated. Changes in mitochondrial functions accompanying sexual differentiation in P. falciparum will be studied. Unusual features of transcription and translation in parasite mitochondria -- generation of numerous transcripts, likelihood of trans-associated mosaic ribosomes -- will be analyzed to understand the underlying mechanisms which may reveal additional targets for antimalarial drug action.