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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：
10736939
负责人：
Sean Taylor PRIGGE
金额：
$ 47.85万
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 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736939
关键词：
Abbreviations Acyl Carrier Protein Address Aspartate Biochemical Pathway Biology Blood Bypass CCI-779 Carbamoyl Transferases Coenzyme A Complement Culicidae Cytosol Deaminase Dependence Dephospho-CoA kinase Development Dihydrofolate Reductase Dihydroorotate dehydrogenase Diphosphates Drug Targeting Drug resistance Engineering Enterobacteria phage P1 Cre recombinase Enzymes Event Ferredoxin Ferredoxin-NADP Reductase Flavin Mononucleotide Functional disorder Future Genes Genetic Genetic Screening Genome Glutamine Goals Human Individual Insertional Mutagenesis Investments Iron Isomerase Knowledge Ligands LoxP-flanked allele Maintenance Malaria Maps Membrane Metabolic Metabolic Pathway Metabolism Methods Molecular NAD(P)+ transhydrogenase Neomycin Nuclear Organelles Oxidoreductase Parasites Pathway interactions Phenotype Plastids Play Process Proteins Research Role S-Adenosylhomocysteine S-Adenosylmethionine Site Source Sulfur System Tacrolimus Binding Proteins Tetracyclines Transposase Vesicle combat cysteine desulfurase design drug development experimental study fatty acid biosynthesis forward genetics genetic approach inhibitor inorganic phosphate insight isopentenyl pyrophosphate isoprenoid knock-down mevalonate nanopore new therapeutic target novel parasite resource protein function protein transport pyruvate dehydrogenase response reverse genetics segregation targeted sequencing therapeutic development therapeutic target tool transmission process zygote

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 isoprenoid precursor IPP (isopentenyl pyrophosphate) survive apicoplast inhibitors - even those which result in disruption of the organelle and loss of the organellar genome. We built on this finding by creating a metabolic bypass parasite line that produces isoprenoid precursors in the cytosol using an engineered four- enzyme mevalonate pathway. We propose to use a combination of genetic approaches in conjunction with metabolic bypass to identify all nuclear-encoded proteins which are essential for apicoplast function and parasite survival. We will also use new conditional tools (knockdown, conditional localization, DiCre) 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。治疗血期寄生虫与类异戊二烯前体 IPP（异戊烯焦磷酸）一起存活的 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。我们在此发现的基础上创建了一个代谢旁路寄生虫系，使用工程化的四-在细胞质中产生类异戊二烯前体酶甲羟戊酸途径。我们建议结合使用遗传方法代谢旁路识别所有核编码蛋白质，这些蛋白质对于顶端质体功能至关重要，并且寄生虫的生存。我们还将使用新的条件工具（knockdown、条件定位、DiCre）来进一步描述特定蛋白质的作用以及与其损失相关的表型。我们的实验将有助于更全面地了解代谢途径和非代谢过程所需的信息顶端质体功能和寄生虫存活。最终，我们打算确定新的目标并验证已知的目标未来开发治疗疟疾和阻止其传播的药物的目标。