Harnessing the Unique Biogenesis of the Apicomplexan plastid organelle forAntimalarial Targets

摘要/项目摘要 由疟原虫寄生虫引起的疟疾是全球发病率和死亡率的主要原因。这个 对一线抗疟疾药物出现耐药性有可能抹去在疾病控制方面取得的进展 并使根除该病毒的努力受挫。迫切需要新的药物靶点来规避目前的耐药性 机械装置。疟原虫和相关人类病原体的独特生物学与它们的比较 哺乳动物宿主，可被用来发现病原体特异性药物靶点，将宿主毒性降至最低。一个 病原体独特生物学的最好例子是非光合体细胞器，或称质外体。 控制质外体生物发生--生长、分裂和遗传--的关键蛋白质 寄生虫的复制仍然是个谜，尽管阻止质外体生物发生的化合物，如 克林霉素，临床上用于预防疟疾和治疗疟疾、巴贝斯虫病和弓形虫病。因为 顶生质体的生物发生在每个增殖期都是必需的，并且在寄生虫之间是保守的，它提出 发现跨生命阶段有效的病原体特异性药物靶点的尚未开发的机会 多种病原体。我们的长期目标是发现质外体生物发生的分子机制和 利用所涉及的机制作为抗疟疾目标。该项目的目标是确定和功能 描述血液期恶性疟原虫液泡体生物发生所需的基因，因为许多必需的，但 到目前为止，这一复杂的过程需要基因。我的实验室已经为 通过成功地设计创新的方法来发现新的分子参与者来实现这一目标。 这项建议将使用新的前锋来确定质外体生物发生所需的先前未知的基因 基因筛选并开始表征新验证基因的生化和细胞功能。通过 鉴定和功能鉴定质外体生物发生蛋白，我们将了解这个过程是如何 可以阻断多种真核病原体在多个阶段的发病机制。

Abstract/ Project summary Malaria caused by Plasmodium spp parasites is a leading cause of morbidity and mortality globally. The emergence of resistance to frontline antimalarial drugs threatens to wipe out progress made in disease control and set back efforts toward eradication. New drug targets are urgently needed to circumvent current resistance mechanisms. The unique biology of Plasmodium spp and related human pathogens, compared to their mammalian hosts, can be leveraged to discover pathogen-specific drug targets that minimize host toxicity. A prime example of the pathogen's distinct biology is the non-photosynthetic plastid organelle, or apicoplast. Critical proteins that govern the biogenesis – growth, division, and inheritance – of the apicoplast during parasite replication remain mysterious, though compounds that block apicoplast biogenesis, such as clindamycin, are used clinically to prevent malaria and treat malaria, babesiosis, and toxoplasmosis. Because apicoplast biogenesis is required in every proliferative stage and conserved among parasites, it presents untapped opportunities to discover pathogen-specific drug targets effective across life stages and against multiple pathogens. Our long-term goal is to discover the molecular mechanisms of apicoplast biogenesis and exploit the machinery involved as antimalarial targets. The objective of this project is to identify and functionally characterize genes required for apicoplast biogenesis in blood-stage P. falciparum, since many essential, but as yet unidentified, genes are required for this complex process. My laboratory has laid the foundation to achieve this objective by successfully designing innovative approaches to discover new molecular players. This proposal will identify previously unknown genes required for apicoplast biogenesis using a new forward genetic screen and begin characterizing the biochemical and cellular functions of newly-validated genes. By identifying and functionally characterizing apicoplast biogenesis proteins, we will understand how this process can be disrupted to block pathogenesis in multiple stages of multiple eukaryotic pathogens.