Post-transcriptional regulation in the malaria parasite blood stage

 描述(申请人提供)：疟疾是世界上最具破坏性的寄生虫病之一，仅在2012年就造成约2.07亿例临床病例和62.7万人死亡。疟疾的主要致病因素是寄生虫在血液中复制，导致严重贫血，在最致命的形式中，感染恶性疟原虫的红细胞阻塞器官的毛细血管，这一现象与致命结果有关。血期复制是多个宿主复杂生命周期的一部分，包括有性和无性阶段，这需要对基因表达进行非常严格的发育控制。我们实验室最近的研究表明，转录后控制是寄生虫发育过程中与毒力相关的某些类型基因的主要参与者。转录后调控机制为药物干预提供了新的潜在靶点。我们最近证实，恶性疟原虫CAF1基因的敲除改变了~20%的基因组表达，显著改变了晚期滋养体毒力基因的表达，以及参与寄生虫复制(出口和入侵)的许多晚期蛋白基因的表达。在其他生物中，CAF1是控制基因表达的主要角色，它作为一种死烯基酶调节细胞质中的mRNA衰退，并作为CCR4-NOT复合体的一部分，调节细胞核中的转录。我们假设CAF1是作为转录后调节因子正确控制恶性疟原虫基因表达所必需的。这些研究的长期目标是了解恶性疟原虫转录后调控机制，以确定适合作为新药物靶点的关键因子。在这里，我们试图通过使用我们现有的CAF1基因敲除和基因表达数据、计算工具和其他生化分析来阐明恶性疟原虫这种调控控制背后的一些机制。此外，我们相信阐明转录后基因调控层背后的机制将产生对恶性疟原虫生物学的独特见解。 并有可能为开发针对寄生虫外泄和入侵的新干预措施提供有价值的信息。

 DESCRIPTION (provided by applicant): Malaria is one of the most devastating parasitic diseases worldwide, responsible for an estimated 207 million clinical cases and 627,000 deaths in 2012 alone. Major virulence factors of malaria are parasite replication in the blood that leads to severe anemia, and in the most lethal form, Plasmodium falciparum-infected red cells block capillaries of organs in a phenomenon linked to lethal outcomes. Blood-stage replication is part of a complex life cycle in multiple hosts involving both sexual and asexual stages that requires very tight developmental control of gene expression. Recent studies in our lab have implicated post-transcriptional control as a major player during parasite development in certain types of genes associated with virulence. The mechanisms of post-transcriptional regulatory control represent new potential targets for drug intervention. We recently demonstrated that a knock- out of the P. falciparum CAF1 gene altered expression of ~20% of the genome, dramatically shifting expression of virulence genes in late trophozoites and many genes of late-stage proteins involved in parasite replication (egress and invasion). In other organisms, CAF1 is a major player controlling gene expression as a deadenylase regulating mRNA decay in the cytoplasm and as part of the CCR4-NOT complex regulating transcription in the nucleus. We hypothesize that CAF1 is integral for proper control of P. falciparum gene expression as a post-transcriptional regulator. The long-term objective of these studies is to understand P. falciparum post-transcriptional regulatory mechanisms to identify key players suitable as novel drug targets. We seek here to elucidate some of the mechanisms behind this regulatory control in P. falciparum by using our existing CAF1 knockout and gene expression data, computational tools and other biochemical assays. Further, we believe that illuminating the mechanisms behind the post-transcriptional layer of gene regulation will yield unique insights into P. falciparum biology and has the potential to provide valuable information for the development of new interventions targeting parasite egress and invasion.