Plasmodium induced new permeation pathways during hepatocyte infection

描述（由申请人提供）：本提案的目的是开发和利用电生理方法来评估疟原虫感染期间肝细胞膜通透性的变化。该方法的建立可以帮助确定肝期寄生虫的发展是否需要新的通透性途径（NPP）。由于许多原因，疟原虫在不同发育阶段与宿主的相互作用一直是一个活跃的研究领域。相互作用的生物学是迷人的，了解寄生虫与其宿主的关系可以导致成功干预策略的合理发展。研究人员所采取的研究宿主-寄生虫关系的方法因不同阶段而各不相同。基因组学、蛋白质组学和基于功能的方法已经被应用。每一种方法都有其优点，最有可能的是对几种疟原虫基因组进行测序，使研究人员能够尝试对寄生虫基因表达进行合理的功能分析。最近的功能研究试图在疟原虫感染的红细胞中确定NPPs，这可能是受感染红细胞膜通透性增加的原因。已经通过多种方法确定了几个npp的例子，但是实际上没有研究表明寄生虫可以修饰肝细胞膜。本提案中概述的研究是新颖的，将试图确定疟原虫感染肝细胞中的NPPs，并在寄生虫细胞内生长和发育的背景下为这些修饰提供功能意义。寄生虫诱导的肝细胞膜修饰的证明不仅可以增加我们对疟原虫代谢过程的理解，而且可以用于验证化疗药物的潜在靶点。公共卫生相关性：疟原虫诱导肝细胞膜修饰的证明不仅增加了我们对寄生虫在肝细胞发育过程中发生的代谢过程的理解，而且可以用于验证化疗药物的潜在靶点。这可能为预防和治疗疟疾提供一种新的途径。

DESCRIPTION (provided by applicant): The objective of this proposal is the development and utilization of electrophysiological methodologies to assess changes in hepatocyte membrane permeability during infection with Plasmodium parasites. The establishment of this methodology could help determine if new permeability pathways (NPP) are required for the development of liver stage parasites. The interaction of the different developmental stages of Plasmodium with the host, in which they reside, has been an active area of research for a number of reasons. The biology of the interaction is fascinating and understanding the relationship of the parasite with its host can lead to the rational development of successful intervention strategies. The approaches that investigators have taken to study the host-parasite relationship are as varied as the different stages. Genomic, proteomic and functional based approaches have been utilized. Each has its advantages and it is most likely the sequencing of several Plasmodium genomes that has allowed investigators to attempt rational functional analysis of parasite gene expression. Recent functional studies have sought to identify NPPs, in Plasmodium infected erythrocytes that may be responsible for the increased permeability of the infected red blood cell membrane. Several examples of NPPs have been identified by multiple methods, however there is virtually no research to suggest that the parasite can modify the hepatocyte membrane. The studies outlined in this proposal are novel and will attempt to identify NPPs in Plasmodium infected hepatocytes and provide a functional significance for these modifications in the context of the parasites intracellular growth and development. The demonstration of parasite induced hepatocyte membrane modifications would not only add to our understanding of Plasmodium metabolic processes, but could serve to validate potential targets for chemotherapeutic agents. PUBLIC HEALTH RELEVANCE: The demonstration of Plasmodium induced hepatocyte membrane modifications would not only add to our understanding of the metabolic processes that occur during development of the parasite in the hepatocyte, but could serve to validate potential targets for chemotherapeutic agents. This could provide a novel approach for the prophylaxis and treatment of malaria.