Harnessing the Unique Biogenesis of the Apicomplexan plastid organelle forAntimalarial Targets

摘要/项目摘要 由疟原虫属寄生虫引起的疟疾是全球发病率和死亡率的主要原因。的 一线抗疟药物出现耐药性有可能使疾病控制方面取得的进展化为乌有 并阻碍根除的努力。迫切需要新的药物靶点来规避当前的耐药性 机制等疟原虫属和相关人类病原体的独特生物学，与其 哺乳动物宿主，可以用来发现病原体特异性药物靶标，使宿主毒性最小化。一 病原体独特生物学的一个主要例子是非光合质体细胞器或顶质体。 关键的蛋白质，控制生物发生-生长，分裂和遗传-顶质体期间 寄生虫的复制仍然是个谜，尽管有些化合物可以阻止顶质体的生物发生， 克林霉素在临床上用于预防疟疾和治疗疟疾、巴贝虫病和弓形虫病。因为 顶质体生物发生在每个增殖阶段都是必需的，并且在寄生虫中是保守的， 未利用的机会，以发现病原体特异性药物靶标有效跨越生命阶段， 多种病原体我们的长期目标是发现顶质体生物发生的分子机制， 利用相关机制作为抗疟目标。该项目的目标是确定和功能 描述血液阶段恶性疟原虫顶质体生物发生所需的基因，因为许多必需的，但 这一复杂过程需要基因，但目前尚未确定。我的实验室已经为 通过成功设计创新方法来发现新的分子参与者来实现这一目标。 这项建议将确定以前未知的基因所需的顶质体生物利用一个新的向前 基因筛选，并开始表征新验证基因的生化和细胞功能。通过 鉴定和功能特性顶质体生物发生蛋白，我们将了解这个过程是如何 可以被破坏以阻断多种真核病原体的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.