Puf-Mediated Translation Control in Plasmodium

描述(由申请人提供)：在疟疾寄生虫中，蛋白质翻译在很大程度上是未知的。更好地了解这一基本的生命过程可能会确定开发新的治疗干预措施的潜在目标。最近的研究揭示了翻译控制在疟疾寄生虫生命周期中的重要作用，特别是在两个宿主之间的过渡阶段。疟原虫基因组编码PUF RNA结合蛋白的四个成员，PUF RNA结合蛋白是真核生物中一种转录特异性翻译调节蛋白家族。PUF蛋白通过与靶mRNAs的3‘非翻译区结合来控制其翻译，从而调节发育。我们最近的工作表明，恶性疟原虫中的PUF成员是蛋白质翻译的主要调节者，在调节性发育方面发挥着重要作用。基于这些观察结果和PUF成员在恶性疟原虫中的不同表达谱，我们假设PUF家族的翻译抑制物通过调节不同基因的翻译来协调寄生虫的发育和阶段转换。为了确定PUF蛋白在恶性疟原虫发育中的作用，我们建议首先通过基因敲除或敲除来表征单个PUF基因在红细胞内发育和阶段转换中的功能，并确定遗传操作如何影响寄生虫的发育。我们将使用互补的方法来获得与PUF蛋白相关的mRNAs的整体视图，并确定特定靶向的途径。本研究中采用的系统方法将提供关于PUF蛋白在调节疟疾寄生虫发育周期中的功能的全面信息，并为真核生物中PUF介导的翻译控制的进化提供新的见解。

DESCRIPTION (provided by applicant): Protein translation is largely unexplored in the malaria parasites. A better understanding of this basic process of life may identify potential targets for developing new therapeutic interventions. Recent studies have revealed the essential roles of translation control during the life cycle of the malaria parasites, especially at the transition stages between the two hosts. The Plasmodium parasite genome encodes four members of Puf RNA-binding proteins, a family of transcript-specific translational regulators in eukaryotes. Puf proteins regulate development by binding to the 3' untranslated regions of the target mRNAs to control their translation. Our recent work shows that a Puf member in P. falciparum is a master regulator of protein translation and plays an important role in regulating sexual development. Based on these observations and different expression profiles of the Puf members in P. falciparum, we hypothesize that the Puf family translational repressors orchestrate parasite development and stage transitions by regulating translation of different sets of genes. To define the roles of Puf proteins in P. falciparum development, we propose to first characterize the functions of individual Puf genes during intraerythrocytic development and stage transitions by genetic knockout or knockdown and determine how the genetic manipulations affect parasite development. We will use complementary approaches to obtain a holistic view of the mRNAs associated with the Puf proteins and to identify pathways that are specifically targeted. The systematic approaches employed in this study will yield comprehensive information about functions of Puf proteins in regulating the developmental cycle of malaria parasites and provide novel insights into the evolution of Puf-mediated translation control in eukaryotes.