Antimalarial Drug Resistance in P. falciparum

恶性疟原虫的抗疟药物耐药性

• 批准号: 8500147
• 负责人: LIWANG CUI
• 金额: $ 31.34万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500147
• 关键词: Address; Anti-malarial drug resistance; Antimalarials; Area; Artemisinins; Back; Biological Assay; Candidate Disease Gene; China; Clinical; Combined Modality Therapy; Complement; Country; Custom; Data; Detection; Disease; Drug resistance; Epidemiology; Evolution; Falciparum Malaria; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Genotype; Heterogeneity; In Vitro; Inhibitory Concentration 50; Laboratories; Linkage Disequilibrium; Malaria; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Multi-Drug Resistance; Mutation; Myanmar; Natural Selections; Parasites; Pattern; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Population; Predisposition; Prevalence; Prevention; Public Health; Recording of previous events; Research; Resistance; Resistance development; SYBR Green I; Sampling; Scanning; Scheme; Single Nucleotide Polymorphism; Site; Southeastern Asia; Surveys; Technology; Testing; Thailand; Transfection; Variant; artemether; artemisinine; artesunate; base; chemotherapy; design; genome wide association study; genome-wide analysis; high throughput screening; mortality; mutant; pressure; research study; resistance mechanism; response; southeast Asian; tool

Multidrug-resistant (MDR) Plasmodium falciparum is partially responsible for the global resurgence of malaria. With the failing of many antimalarial drugs, most malaria-endemic countries have changed to artemisinin-based combination therapies (ACTs). Although ACT is highly effective, recent detection of reduced sensitivity in P. falciparum to artemisinins in several regions of Southeast Asia has raised great concerns. Although early resistance detection is essential for deterring and containing resistance, current detection of artemisinin resistance relies exclusively on clinical observations and in vitro drug assays. The lack of understanding of the exact mode of action and the mechanism of resistance for artemisinins makes resistance surveillance in areas of artemisinin deployment very difficult. To address this urgent problem, we have selected Thailand, China's Yunnan and Myanmar as our strategic sites to investigate artemisinin resistance. Southeast Asia has been the epicenter of drug resistant malaria parasites. The prevalence of MDR parasites, extensive deployment of artemisinins often as monotherapy, and the detection of reduced susceptibility to artemisinins among parasite populations suggest that artemisinin resistance is likely to arise in this region. In this study, we propose to 1) systematically sample P. falciparum clinical isolates and accurately determine their in vitro sensitivity to a panel of antimalarial drugs including artemisinins; 2) determine the correlations of artemisinin-resistance with polymorphisms in the genome using both candidate gene and genome-wide association study (GWAS) approaches; 3) validate promising mutations within candidate genes through allelic exchange experiments; and 4) develop molecular methods for detecting the mutation(s) responsible for artemisinin resistance and perform field surveillance of the resistance marker(s). The integration of a comprehensive sampling scheme, accurate in vitro drug assays and GWAS will provide essential information for elucidating the mechanism of artemisinin resistance, understanding how artemisinin resistance evolves, and facilitating the design of molecular methods to closely monitor resistance development in areas of ACT deployment.

恶性疟原虫抗多药（MDR）疟原虫部分负责疟疾的全球复苏。随着许多抗疟药的失败，大多数疟疾流行国家都变成了基于青蒿素的组合疗法（ACTS）。尽管行为是高效的，但最近发现在东南亚几个地区，恶性疟原虫对青蒿素的敏感性降低引起了极大的关注。尽管早期耐药性检测对于阻止和含有耐药性至关重要，但当前对青蒿素耐药性的检测仅取决于临床观察和体外药物测定。缺乏对精确作用方式的了解和青蒿素抗性机制，因此非常困难地在青蒿素部署领域的耐药性监测。为了解决这一紧急问题，我们选择了泰国，中国的云南和缅甸作为我们的战略遗址来调查阿甘米辛蛋白的抵抗。东南亚一直是抗药性疟疾寄生虫的中心。 MDR寄生虫的患病率，通常是单一疗法的大噻天胺胺部署，以及寄生虫种群中青蒿素易感性降低的发现，这表明该地区可能会出现青蒿素耐药性。在这项研究中，我们建议1）系统地采样恶性疟原虫临床分离株，并准确地确定它们对包括青蒿素在内的抗疟药小组的体外敏感性； 2）使用候选基因和全基因组关联研究（GWAS）方法来确定青蒿素抗性与基因组中多态性的相关性； 3）通过等位基因交换实验验证候选基因内的有希望的突变；和4）开发用于检测负责青蒿素耐药性突变的分子方法，并执行耐药标记的现场监测。 精确的体外药物测定和GWAS的整合，将为阐明青蒿素耐药性机理提供必不可少的信息，了解青蒿素耐药性如何演变，并促进分子方法设计的设计，以密切监测ACT部署区域的耐药性发展。