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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.

疟疾寄生虫含有一种被称为顶质体的质体细胞器，这是寄生虫在体内生存所必需的