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：
9914084
负责人：
Sean Taylor PRIGGE
金额：
$ 40.5万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914084
关键词：
Address Affect Anabolism Biochemical Pathway Biology Blood Bypass Culicidae Dependence Drug Targeting Drug resistance Event Functional disorder Future Genes Genetic Genetic Screening Genetic Transcription 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 Sulfur System Techniques Testing combat design drug development experimental study forward genetics genetic approach genetic manipulation genome editing inhibitor/antagonist insight isopentenyl pyrophosphate mevalonate mutant new therapeutic target novel parasite resource protein transport response reverse genetics segregation therapeutic development therapeutic target tool 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.

疟疾寄生虫包含一个称为寄生虫生存所需的质体细胞器人类和向蚊子传播。长期以来，apicoplast被认为是重要的来源然而，新药物目标以应对不可避免的耐药性问题，事实证明，它很难识别和验证对寄生虫生存至关重要的蛋白质蛋白。这个目标现在可以实现使用新的遗传工具与apicopollast的代谢旁路结合使用。治疗的血液阶段寄生虫伴有异戊二烯化合物IPP（等苯基焦磷酸盐）生存的膜型抑制剂 - 甚至导致细胞器的破坏和细胞器基因组的丧失。最近，我们使用了IPP代谢绕过以证明铁硫簇生物合成对于维持细胞器至关重要。我们建议与代谢旁路结合使用反向和前进的遗传方法来识别其他核编码的蛋白质对于凋亡功能和寄生虫存活至关重要。我们还将使用新的条件定位工具，以进一步表征特定蛋白质和表型的作用与他们的损失相关。我们的实验将有助于建立代谢的更完整的图片 Apicoplast功能和寄生虫存活所需的途径和非代谢过程。最终，我们打算识别新的靶标并验证已知的靶标，以使药物的未来开发以治愈疟疾并停止其传输。