ORGANELLE GENOMES OF MALARIAL PARASITES

这个项目的长期目标是了解线粒体 疟疾寄生虫遗传系统，以评估线粒体生理学， 并评估线粒体对抗疟疾药物的反应。在.期间 在过去的几年里，很明显疟疾寄生虫--确实， 所有的顶端复合体--都含有两个非常不寻常的细胞质基因组：一个是6- Kb DNA元素，在这个实验室中发现，似乎是 线粒体基因组，另一个是35kb的环状DNA，之前 被认为是线粒体DNA，现在被认为是叶绿体 具有未知函数的导数。这些基因组代表着非常 不寻常的遗传系统，并存在于已被证实或 潜在的抗疟疾药物作用场所。这一点越来越明显 除了氧化磷脂，线粒体也起着至关重要的作用 在大多数真核生物的许多代谢步骤中扮演的角色。干扰 这些功能不利于这些生物的生存。这个 该项目的中心假设是线粒体功能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的领域的进展。 在开发了某些新的方法和试剂后，这个实验室 建议应用它们来促进对线粒体的理解 疟疾寄生虫。抗疟疾化合物的作用，如 线粒体电子上的羟基萘醌和8-氨基喹啉 恶性疟原虫和约氏疟原虫的转运将通过 监测膜电位和呼吸作用。分子机制 对这些药物的潜在耐药性将进行调查。中的更改 线粒体功能伴随着有性分化。 将对恶性疟原虫进行研究。不同寻常的转录和转录特征 寄生虫线粒体的翻译--大量转录本的产生， 反式相关的镶嵌核糖体的可能性--将被分析到 了解可能揭示其他目标的潜在机制 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.