A large-scale transposon mutagenesis screen of Plasmodium falciparum

描述（由申请人提供）：疟疾是人类死亡和疾病的主要原因，每年造成3亿多例临床疟疾病例和100多万例死亡。控制和治疗疟疾的传统措施越来越不有效，迫切需要开发新的药物和疫苗。开发新的抗疟疾疗法的一个战略障碍仍然是缺乏关于大多数恶性疟原虫基因的实验验证的功能信息。识别新药靶点的关键是更好地了解寄生虫生理学中的基本代谢途径和弱点。我们的方法将创建一个大型的恶性疟原虫突变体克隆库，该库具有单个piggyBac插入，将用于表型分析。初步研究已经验证了这种方法能够识别血液阶段生长的关键过程。通过这个项目，我们希望确定几十个对寄生虫毒力和发育过程至关重要的基因，这些基因是可以启动药物发现项目的新靶点。我们项目的另一个重要成果将为疟疾研究界提供大量基因敲除，这将是许多其他研究项目的宝贵资源。 公共卫生相关性：疟疾是一个毁灭性的全球健康问题，消除它作为一种重要的疾病需要新的疗法。开发新的抗疟疾药物的一个主要障碍是缺乏关于最佳靶点的全面信息。针对疟疾寄生虫中多种不同靶标有效的新药对于有效消除疟疾至关重要。我们的项目将提供这种类型的知识，以确定新的药物靶点。

DESCRIPTION (provided by applicant): Malaria is a leading cause of human death and illness, causing over 300 million cases of clinical malaria and 1+ million deaths each year. Traditional measures to control and cure malaria are becoming increasingly less effective and there is an urgent need for the development of new drugs and vaccines. A strategic hurdle for development of new anti-malarial therapeutics remains the lack of experimentally validated functional information about most P. falciparum genes. Critical for identification of new drug targets is a better understanding of essential metabolic pathways and weaknesses in the parasite's physiology. Our approach will create a large library of P. falciparum parasite mutant clones with single piggyBac insertions that will be used for phenotypic analysis. Preliminary studies have validated this approach to be able to identify processes critical for blood-stage growth. Through this project we expect to identify dozens of genes critical for parasite virulence and development processes that are novel targets on which drug discovery projects can be initiated. An additional important outcome of our project will provide the malaria research community with a large collection of gene knockouts that will be a valuable resource for a multitude of other research projects. PUBLIC HEALTH RELEVANCE: Malaria is a devastating global health problem and its elimination as an important disease requires new therapies. A major hurdle for development of new an anti-malarial drug is a lack of comprehensive information about the best targets. New drugs effective against multiple different targets in malaria parasites are essential to effectively eliminate malaria. Our project will provide this type of knowledge to identify new drug targets.