Biology of the Apicomplexan Plastid

顶复体质体的生物学

• 批准号: 7319647
• 负责人: BORIS STRIEPEN
• 金额: $ 28.04万
• 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/7319647
• 关键词: Affect; Algae; Antibodies; Antiparasitic Agents; Apicomplexa; Bioinformatics; Biological; Biological Assay; Biology; Cell Cycle; Cell division; Cells; Cellular biology; Centrosome; Chloroplasts; Chromosome Segregation; Chronic; Chronology; Comparative Genomic Analysis; Compatible; Complement; Cryptosporidiosis; Cryptosporidium; DNA-Directed DNA Polymerase; Data; Development; Disease; Drug Delivery Systems; Elements; Event; Fluorescence; Gene Proteins; Genes; Genetic; Genetic Screening; Genome; Genomics; HU Protein; Hand; Histones; Homologous Gene; Human; Laser Microscopy; Lead; Livestock; Maintenance; Malaria; Microscopic; Mitotic spindle; Modeling; Molecular; Multi-Drug Resistance; Numbers; Organelles; Organism; Parasites; Pathogenesis; Pathway interactions; Pharmacological Treatment; Phenotype; Phylogenetic Analysis; Phylogeny; Plants; Plasmodium; Plastids; Positioning Attribute; Process; Protein Overexpression; Purpose; Research Personnel; Resources; Role; Staging; Testing; Time; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Tubulin; antimicrobial drug; base; biodefense; comparative; daughter cell; drug development; fascinate; gene cloning; genetic analysis; genome sequencing; in vivo; interest; knock-down; mutant; pathogen; physical model; programs; protein function; research study; segregation

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.

顶复门包含一个大的原生动物寄生虫负责许多重要的 人畜疾病。其中几种生物（弓形虫，隐孢子虫和环孢子虫）是 也被列为潜在生物防御关注的B型病原体。在联合国系统内仍然存在重大挑战， 抗微生物药物治疗这些疾病。一个残余的叶绿体，顶质体的发现， 提出了几种寄生虫特异性途径，可以作为特定的药物靶点，以帮助克服 其中的一些挑战。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展和发病机制，确认其为靶标，并证明 细胞器对于生物体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。 植物和藻类的叶绿体分裂机制依赖于蓝藻的叶绿体基因 起源，其中细菌微管蛋白同系物ftsZ是最突出的。我们的基因组分析 在顶复门中发现了这些基因的任何明显同源物。在缺乏蛋白质的情况下， 保存的机器？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， 顶复门中的质体是用一种真正的真核机制分离的， 有丝分裂纺锤体的中心体。该提案提出了一些机械模型来解释如何 质体被忠实地分离成子细胞，分裂是如何发生的，在寄生虫细胞内是定时的， 循环，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。测试 这些假设，我们已经组装了一套高度兼容的细胞生物学，比较基因组学和 基因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， 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。