Conditional probes of secretory protein function in malaria parasites

描述（由申请人提供）：控制蛋白质水平的遗传方法是探索任何生物体基础生物学的极有价值的工具。两种常用的工具是RNA干扰和条件表达，这两种工具都没有成功地应用于疟疾研究。我们正在开发一种新的方法来控制疟原虫分泌途径中的蛋白质。恶性疟原虫基因组编码的超过20%的蛋白质被认为是通过分泌系统到达细胞器或细胞外目的地。这些蛋白质在寄生虫代谢、营养获取、入侵、宿主细胞重塑和寄生虫生物学的其他关键方面具有关键作用。本项目的目标是设计和优化条件探针来控制恶性疟原虫可溶性分泌蛋白的定位。然后将通过将其应用于两个生物靶标来验证该方法：一个在顶质体细胞器中，一个驻留在寄生虫液泡中。成功开发条件定位工具将增强我们探测疟原虫基本生物学的能力，并使我们能够验证潜在的 治疗干预的目标。 公共卫生相关性：抗药性疟疾寄生虫的不可避免的增加创造了开发新的控制策略的持续需求。我们正在开发一种遗传工具，这将有助于探索基本的寄生虫生物学和验证新的药物靶点。

DESCRIPTION (provided by applicant): Genetic methods to control protein levels are extremely valuable tools for probing the basic biology of any organism. Two commonly employed tools are RNA interference and conditional expression, neither of which has been successfully implemented in malaria research. We are developing a new method to control proteins in the secretory pathway of malaria parasites. Over 20% of the proteins encoded by the Plasmodium falciparum genome are thought to pass through the secretory system on their way to organellar or extracellular destinations. These proteins have key roles in parasite metabolism, nutrient acquisition, invasion, host cell remodeling, and other critical aspects of parasite biolog. The goal of this project is to design and optimize a conditional probe to control the localization f soluble secretory proteins in P. falciparum. This method will then be validated by applying it to two biological targets: one in the apicoplast organelle and one which resides in the parasitophorous vacuole. Successful development of a conditional localization tool will enhance our ability to probe the basic biology of malaria parasites and will allow us to validate potential targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The inevitable rise of drug-resistant malaria parasites creates a continuing need to develop new control strategies. We are developing a genetic tool that will help to probe basic parasite biology and validate new drug targets.