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PfVP1, a battery of the malaria parasite, is critical for ring stage development

PfVP1 是疟疾寄生虫的一组，对于环期发育至关重要

基本信息

批准号：
10300573
负责人：
Hangjun Ke
金额：
$ 18.82万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-10 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300573
关键词：
Affinity Antimalarials Archaea Bacteria Biochemical Bioenergetics Biological Biology Blood Budgets CRISPR/Cas technology Cell membrane Cells Complement Consumption Contracts DNA biosynthesis Data Development Diphosphates Drug resistance Energy Supply Energy-Generating Resources Erythrocytes Future Genetic Glucose Glycolysis Human Hydrolysis Knock-out Malaria Mammalian Cell Measures Mediating Membrane Metabolic Molecular Target Mutagenesis Mutate Nutrient Organism Oxidative Phosphorylation Parasites Persons Physiological Plants Plasmodium falciparum Process Proteins Proton Pump Protons RNA Reaction Regulatory Element Resistance Resistance development Risk Role Route Running Saccharomyces cerevisiae Testing Time Vacuole Vesicle Waste Products Yeasts asexual base cost drug development fungus genomic locus global health insight knock-down metabolic rate nutrition pyrophosphatase sodium ion uptake

项目摘要

Project Summary Malaria remains a major global health concern and the control progress has run into a serious bottleneck in recent years. Each year, more than 3 billion people are living at risk of contracting malaria, 200 million people are infected and half a million people die from malaria. As malaria parasites rapidly develop resistance to available antimalarial drugs, a better understanding of fundamental biology is urgently needed. In the asexual blood stages, malaria parasites mainly reply on glycolysis for energy since the parasite's mitochondrion does not perform oxidative phosphorylation to produce ATP. They also contain membrane bound proton pumping pyrophosphatases (mPPases), which use pyrophosphate, the by-product of over 200 cellular reactions, as the energy source to pump protons across a membrane. We have previously knocked out PfVP2 (PF3D7_1235200) whereas PfVP1 (PF3D7_1456800) has been predicted to be essential. Using a CRISPR/Cas9 mediated genetic tagging/conditional knockdown, we have found that PfVP1 is localized to the parasite plasma membrane and is essential for ring stage development. In this application, we hypothesize that PfVP1 uses pyrophosphate as an alternative energy source to sustain a proton electrochemical gradient in the ring stage development of Plasmodium falciparum. We will test this hypothesis in the following aims. Aim 1, Assess the activity of PfVP1 as an integral membrane proton-pumping pyrophosphatase. Aim 2, Define the function of PfVP1 in ring stage parasites. Together, this proposal will uncover important insights of ring stage development and bioenergetics, critical yet understudied aspects of parasite biology. If successful, the studies proposed here will provide direct evidence that an alternative energy source is critical for early stage development of a malaria parasite in RBCs. Finding a critical molecular target at the ring stage will also facilitate target-based drug development in future to better inhibit metabolically less active parasite forms that are often resistant to current antimalarials.

项目摘要疟疾仍然是一个主要的全球卫生问题，控制进展已经遇到了严重的近几年的瓶颈问题。每年有超过30亿人生活在感染的风险中疟疾，2亿人被感染，50万人死于疟疾。作为疟疾寄生虫对可用的抗疟疾药物迅速产生抗药性，更好地了解迫切需要基础生物学。在无性血液阶段，疟疾寄生虫主要是回答糖酵解以获取能量，因为寄生虫的线粒体不进行氧化磷酸化以产生三磷酸腺苷。它们还含有膜结合的质子泵浦。焦磷酸酶(MPPase)，它利用200多个细胞的副产物焦磷酸盐化学反应，作为将质子泵过膜的能量来源。我们之前已经 PfVP2(Pf3D7_1235200)敲除，而PfVP1(Pf3D7_1456800)已被预测是必不可少的。使用CRISPR/Cas9介导的遗传标签/条件敲除，我们已发现PfVP1定位于寄生虫的质膜，对环是必需的阶段性发展。在这个应用中，我们假设PfVP1使用焦磷酸盐作为在环形阶段维持质子电化学梯度的替代能源恶性疟原虫的发育。我们将在以下目标中检验这一假设。目的1、评价PfVP1作为整膜质子泵焦磷酸酶的活性。目的2，明确PfVP1在环期寄生虫中的功能。总之，这项提案将揭示环阶段发育和生物能量学的重要见解，关键但研究不足寄生虫生物学的各个方面。如果成功，这里提出的研究将提供直接的证据替代能源对疟疾寄生虫的早期发展至关重要红细胞。在环阶段找到关键的分子靶点也将有助于靶向药物的开发未来开发更好地抑制新陈代谢不太活跃的寄生虫形式对当前的抗疟疾药物有抵抗力。