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（由适用提供）：疟疾是全世界最具破坏性的寄生虫病之一，仅在2012年就导致了估计的2.07亿个临床病例和627,000例死亡。疟疾的主要病毒因子是血液中导致严重贫血的寄生虫复制，并且在最致命的形式下，感染的恶性疟原虫感染的红细胞阻止了与致命结局有关的现象的器官的毛细血管。血液阶段复制是多个宿主的复杂生命周期的一部分，涉及性和无性阶段，需要非常严格的基因表达的发育控制。我们实验室中的最新研究已在与病毒相关的某些类型的基因中实施了转录后控制作为主要参与者。转录后调节控制的机制代表了药物干预的新潜在目标。我们最近证明，恶性疟原虫Caf1基因的敲除改变了〜20％的基因组的表达，在晚期滋养体中的病毒基因的表达发生了巨大转移，并且许多参与寄生虫复制的后期蛋白的基因（Egress and Invesion）。在其他生物体中，CAF1是控制基因表达的主要参与者，作为细胞质中的deenenylase调节mRNA衰减，作为CCR4-ccr4-核中的一部分，不调节核中的调节转录。我们假设CAF1是适当控制恶性疟原虫基因表达作为转录后调节剂的组成部分。这些研究的长期目的是了解法规后恶性疟原虫的调节机制，以确定合适的药物作为新药物靶标的关键参与者。我们在这里寻求通过使用现有的CAF1基因敲除和基因表达数据，计算工具和其他生化测定法，以阐明恶性疟原虫中这种调节性控制背后的一些机制。此外，我们认为，阐明基因调节后列出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出口和入侵的新干预措施提供有价值的信息。