权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Determinants of apicoplast maintenance in malaria parasites

疟原虫顶质体维持的决定因素

基本信息

批准号：
9159090
负责人：
Sean Taylor PRIGGE
金额：
$ 38.33万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-20 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9159090
关键词：
Address Affect Anabolism Biochemical Pathway Biology Blood Bypass Culicidae Dependence Development Drug Targeting Drug resistance Event Functional disorder Future Genes Genetic Genetic Screening Genome Goals Human Individual Investments Iron Isoprene Knowledge Ligands Maintenance Malaria Maps Membrane Metabolic Metabolic Pathway Metabolism Molecular Genetics Morphology Mutagenesis Mutation Nuclear Organelles Parasites Phenotype Plastids Play Process Proteins Research Role Series Source Staging Sulfur System Techniques Testing combat design drug development forward genetics genetic approach genetic manipulation genome editing inhibitor/antagonist insight isopentenyl pyrophosphate mevalonate mutant new therapeutic target novel parasite resource protein transport research study response reverse genetics segregation therapeutic target tool trafficking transmission process

项目摘要

Malaria parasites contain a plastid organelle called the apicoplast that is required for parasite survival in humans and for transmission to mosquitoes. The apicoplast has long been recognized as an important source of new drug targets to combat the inevitable problem of drug resistance, however, it has proven difficult to identify and validate apicoplast proteins that are essential for parasite survival. This goal is now achievable using new genetic tools in combination with metabolic bypass of the apicoplast. Blood stage parasites treated with the isoprene compound IPP (isopentenyl pyrophosphate) survive apicoplast inhibitors - even those which result in disruption of the organelle and loss of the organellar genome. Recently, we used the IPP metabolic bypass to demonstrate that iron-sulfur cluster biosynthesis is essential for maintenance of the organelle. We propose to use reverse and forward genetic approaches in conjunction with metabolic bypass to identify other nuclear-encoded proteins which are essential for apicoplast function and parasite survival. We will also use a new conditional localization tool to further characterize the roles of specific proteins and the phenotypes associated with their loss. Our experiments will help to build a more complete picture of the metabolic pathways and non-metabolic processes required for apicoplast function and parasite survival. Ultimately, we intend to identify novel targets and to validate known targets for future development of drugs to cure malaria and stop its transmission.

疟原虫含有一种称为顶端质体的质体细胞器，这是疟原虫生存所必需的。人类以及传播给蚊子。顶端质体长期以来被认为是重要的来源寻找新的药物靶点来应对不可避免的耐药性问题，然而，事实证明很难识别并验证对寄生虫生存至关重要的顶质体蛋白。这个目标现在可以实现使用新的遗传工具与顶质体的代谢旁路相结合。治疗血期寄生虫与异戊二烯化合物 IPP（异戊烯基焦磷酸盐）一起存在的 apicoplast 抑制剂 - 即使是那些导致细胞器破坏和细胞器基因组丢失。最近，我们使用IPP代谢旁路以证明铁硫簇生物合成对于细胞器的维持至关重要。我们建议使用反向和正向遗传方法结合代谢旁路来识别其他核编码蛋白，对顶端质体功能和寄生虫生存至关重要。我们还将使用一个新的条件定位工具可进一步表征特定蛋白质的作用和表型与他们的损失有关。我们的实验将有助于建立更完整的代谢图景顶端质体功能和寄生虫生存所需的途径和非代谢过程。最终，我们打算确定新的目标并验证已知的目标，以用于未来开发治疗疟疾的药物并停止其传输。