Biology of the Apicomplexan Plastid

顶复体质体的生物学

• 批准号: 7024189
• 负责人: BORIS STRIEPEN
• 金额: $ 29.44万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024189
• 关键词: Apicomplexa; DNA directed DNA polymerase; Toxoplasma gondii; bioinformatics; cell biology; centrosome; chromosome movement; gene expression; genetic screening; genetically modified animals; histones; laboratory mouse; microscopy; molecular cloning; mutant; organelles; protein localization; protein quantitation /detection; protein structure function; protozoal genetics

DESCRIPTION (provided by applicant): The phylum Apicomplexa contains a large group of protozoan parasites responsible for numerous important human and livestock diseases. Several of these organisms (Toxoplasma, Cryptosporidium & Cyclospora) 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 overwhelmingly on 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.

描述（由申请人提供）：顶复门包含一大类原生动物寄生虫，可引起许多重要的人类和牲畜疾病。其中几种生物（弓形虫、隐孢子虫和环孢子虫）也被列为潜在生物防御关注的B型病原体。在这些疾病的抗微生物药物治疗中仍然存在重大挑战。残余叶绿体（顶质体）的发现，现在提出了几种寄生虫特异性途径，可以作为特异性药物靶标来帮助克服其中一些挑战。基因组学、遗传学和药理学数据表明，顶质体对于疟原虫和弓形虫的发育和发病机理是必不可少的，从而验证了顶质体作为靶标的重要性，并证明了顶质体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忠实地复制和分离这个重要的细胞器及其基因组所使用的机制。 植物和藻类中的叶绿体分裂机制主要依赖于蓝藻起源的基因，其中细菌微管蛋白同源物ftsZ是最突出的。我们的基因组分析没有发现任何明确的同源基因的顶复门。在缺乏保守机制的情况下，顶质体是如何分裂的？基于我们的细胞生物学研究，我们假设，在鲜明对比的植物的质体在Apicomplexa分离使用一个真正的真核机制-协会与有丝分裂纺锤体的中心体。这个提议发展了许多机制模型来解释质体如何忠实地分离成子细胞，裂变如何发生，以及寄生虫细胞周期内的时间，以及细胞器基因组的复制和维持如何与这个过程联系在一起。为了验证这些假设，我们已经组装了一套高度兼容的细胞生物学，比较基因组和遗传实验。基因组和遗传筛选将使我们能够进一步完善我们的假设，并将帮助我们在现有的基因和蛋白质之外用更多的分子参与者来填充它们。