Post-transcriptional regulation in the malaria parasite blood stage

疟疾寄生虫血液阶段的转录后调控

• 批准号: 9055547
• 负责人: Jenna Oberstaller
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2018-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055547
• 关键词: Affinity Chromatography; Anemia; Antibodies; Biochemical; Bioinformatics; Biological Assay; Biology; Blood; Blood capillaries; Boxing; Cell Nucleus; Cessation of life; Clinical; Complement; Complex; Cytoplasm; Data; Development; Drug Targeting; Erythrocytes; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Goals; Intervention; Knock-out; Life Cycle Stages; Link; Malaria; Messenger RNA; Methods; Mutagenesis; Organ; Organism; Outcome; Parasites; Parasitic Diseases; Phenotype; Plasmids; Plasmodium; Plasmodium falciparum; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Recombinants; Regulation; Regulator Genes; Regulon; Reporter; Staging; Transcript; Virulence; Virulence Factors; asexual; capillary; computerized tools; crosslink; design; insight; knockout gene; mRNA Decay; mutant; new therapeutic target; next generation sequencing; public health relevance; research study; tool; whole blood lead

 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.

 描述（由申请人提供）：疟疾是世界上最具破坏性的寄生虫病之一，仅在2012年就造成估计2.07亿例临床病例和627，000例死亡。疟疾的主要毒力因子是血液中的寄生虫复制，导致严重贫血，并且在最致命的形式中，恶性疟原虫感染的红细胞阻塞器官的毛细血管，这种现象与致命结果有关。血液阶段的复制是一个复杂的生命周期的一部分，在多个主机涉及有性和无性阶段，需要非常严格的基因表达的发育控制。我们实验室最近的研究表明，转录后控制在某些类型的与毒力相关的基因中是寄生虫发育过程中的主要参与者。转录后调控的机制代表了药物干预的新的潜在靶点。我们最近证明，恶性疟原虫CAF 1基因的敲除改变了约20%基因组的表达，显著改变了晚期滋养体中毒力基因的表达和参与寄生虫复制（外出和入侵）的晚期蛋白质的许多基因。在其他生物体中，CAF 1是控制基因表达的主要参与者，作为去腺苷酶调节细胞质中的mRNA衰变，并作为CCR 4-NOT复合物的一部分调节细胞核中的转录。我们假设CAF 1作为一个转录后调节因子，对恶性疟原虫基因表达的正确控制是不可或缺的。这些研究的长期目标是了解恶性疟原虫的转录后调控机制，以确定适合作为新型药物靶点的关键参与者。我们试图在这里阐明一些机制背后的调控恶性疟原虫通过使用我们现有的CAF 1基因敲除和基因表达数据，计算工具和其他生化检测。此外，我们相信，阐明基因调控的转录后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出和入侵的新干预措施提供有价值的信息。