Biology of the Apicomplexan Plastid

Apicomplexa包含一大群原生动物寄生虫，这些寄生虫对许多重要的 人类和家畜疾病。其中几种生物(弓形虫、隐孢子虫和环孢子虫)是 也被列为潜在的生物防御问题的B型病原体。重大挑战仍然存在 针对这些疾病的抗微生物药物治疗。发现了残存的叶绿体，即质外体 介绍了几种寄生虫的特定途径，这些途径可以作为特定的药物靶点来帮助克服 其中一些挑战。基因组、遗传学和药理学数据表明，质外体是 疟原虫和弓形虫的发展和致病机制验证其作为靶标和论证 细胞器对于生物体生物学的重要性。这项提案的重点是解开 寄生虫用来忠实地复制和分离这个重要的细胞器及其基因组的机制。 植物和藻类中的叶绿体分裂机制依赖于蓝藻的糖蛋白基因 起源，其中细菌微管蛋白同源物FtsZ最为突出。我们的基因组分析还没有 在Apicomplexa中发现了这些基因的任何明确的同源基因。在无菌条件下，质外体是如何分裂的 保守的机器？基于我们的细胞生物学研究，我们假设与植物形成鲜明对比的是 顶端复合体中的叶绿体是用真正的真核机制分离的。 有丝分裂纺锤体的中心体。这一建议开发了许多机械模型来解释如何 质体被忠实地分离成子细胞，如何在寄生虫细胞内发生分裂和计时- 周期，以及细胞器基因组的复制和维持如何与这一过程联系在一起。为了测试 这些假说我们已经组装了一套高度兼容的细胞生物学、比较基因组学和 基因实验。基因组和基因筛查将允许我们进一步完善我们的假设，并将 帮助我们在已有的基因和蛋白质之外，用更多的分子参与者来填充它们。

The phylumApicomplexa contains a large group of protozoan parasites responsible for numerousimportant human and livestock diseases. Several of these organisms (Toxoplasma, Cryptosporidium & Cyclospord) are also listed as type B pathogens of potential biodefense concern. Significant challenges remain in the antimicrobial drug treatment for these diseases. The discovery of a remnant chloroplast, the apicoplast, now presents several parasite specific pathways that can be exploited as specific drug targets to help overcome some of these challenges. Genomie, genetic and pharmacological data show that the apicoplast is essential for development and pathogenesis for Plasmodium and Toxoplasma validating it as a target and demonstrating the importance of the organelle for the biology of the organism. This proposal is focused on unraveling the mechanisms used by the parasite to faithfully replicate and segregate this important organelle and its genome. The chloroplast division machinery in plants and algae depends overwhelminglyon genes of cyanobacterial origin, with the bacterial tubulin homolog ftsZ being the most prominent. Our genomic analysis has not identified any clear homologs of these genes in Apicomplexa. How is the apicoplast divided in the absence of the conserved machinery? Based on our cell biological studies we hypothesize that in sharp contrast to plants the plastid in Apicomplexa is segregated using a genuinely eukaryotic mechanism ¿association with the centrosomes of the mitotic spindle. This proposal develops a number of mechanistic models to explain how the plastid is faithfully segregated into daughter cells, how fission occurs and is timed within the parasite cell- cycle, and how the replication and maintenance of the organellar genome is tied into this process. To test these hypotheses we have assembled a set of highly compatible cell biological, comparative genomic and genetic experiments. Genomic and genetic screens will permit us to further refine our hypotheses, and will help us to populate them with additional molecular players beyond the genes and proteins already in hand.