Discovering the essential genome of Plasmodium falciparum

项目摘要/摘要 疟疾是人类死亡和疾病的主要原因，导致超过2亿的临床疟疾病例。 每年有40万人死亡。控制和治愈疟疾的传统措施正变得越来越多 效果较差，迫切需要开发新药和疫苗。具有战略意义的 开发新的抗疟疾疗法的障碍仍然是缺乏实验验证 关于大多数恶性疟原虫基因的功能信息。这是一个严重的知识鸿沟。 阻碍新药和疫苗的鉴定。因此，这些新疗法的有效开发 需要更好地了解寄生虫的基本代谢途径和弱点 生理学报告目标。我们的方法是利用功能基因组学研究来确定P. 恶性疟原虫通过全基因组饱和水平的iggyBac诱变和正向遗传筛选。 初步研究已经验证了这种方法，以确定基本的和可有可无的过程 理想的体外培养条件下的无性血期生长。我们将扩展这些研究，以确定 对体内存活至关重要的因素也是如此。通过这个项目，我们希望找出大多数关键的基因 寄生虫在血液阶段的生长和发育有助于识别和优先考虑哪种药物的新靶点 并且可以启动疫苗发现项目。此外，该项目还将为疟疾研究提供 拥有大量对许多其他研究项目有价值的基因敲除的社区。

Project Summary/Abstract Malaria is a leading cause of human death and illness, causing over 200 million cases of clinical malaria and 400,000 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 Plasmodium falciparum genes. This is a critical gap of knowledge hindering identification of new drugs and vaccines. Therefore, efficient development of these new therapies requires a better understanding of essential metabolic pathways and weaknesses in the parasite’s physiology to target. Our approach is to use functional genomics studies to identify essential genes of P. falciparum through whole genome saturation-level piggyBac mutagenesis and forward genetic screens. Preliminary studies have validated this approach to identify essential and dispensable processes for asexual blood-stage growth under ideal in vitro culture conditions. We will extend these studies to identify factors essential for in vivo survival, too. Through this project, we expect to identify most genes critical for parasite blood-stage growth and development helping to identify and prioritize novel targets on which drug and vaccine discovery projects can be initiated. In addition, this project will provide the malaria research community with a large collection of gene knockouts valuable for many other research projects.