Mapping Drug Resistance Genes in Plasmodium Falciparum

绘制恶性疟原虫的耐药基因图谱

• 批准号: 8128037
• 负责人: Tim J Anderson
• 金额: $ 20.71万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-13 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128037
• 关键词: Aftercare; Alleles; Antimalarials; Artemisinins; Candidate Disease Gene; Chromosomes, Human, Pair 5; Clinic; Clinical; Collaborations; Drug resistance; Effectiveness; Evolution; Funding; Gene Mutation; Genes; Genetic Polymorphism; Genome; Genotype; Laboratories; Location; Malaria; Maps; Measures; Medicine; Microsatellite Repeats; Monitor; Mutation; Myanmar; Nucleotides; Parasites; Patients; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Point Mutation; Public Health; Quantitative Trait Loci; Recrudescences; Research; Resistance; Running; Sampling; Screening Result; Series; Thailand; Transfection; Treatment Efficacy; Treatment Failure; Work; artemisinine; clinically relevant; college; comparative; efficacy trial; follow-up; improved; in vivo; killings; mortality; research study; response; tool

Drug resistance is the major obstacle to control of malaria and the spread of resistance has increased malaria mortality over recent decades. Identification of parasite genes that influence drug response would improve our ability to monitor resistance spread, provide tools for better understanding the mode of action of antimalarials, and allow rational redesign of existing drugs. In Thailand the problem is particularly severe with high levels of resistance to all classes of antimalarials except for the artemisinin derivatives. In the initial funding period of this project we measured response to eight drugs in 825 parasite isolates from a single clinic on the Thailand-Burma border, and then genotyped 323 single-clone parasites using 426 di-nucleotide microsatellite markers spaced at 50kb (~3cM) intervals throughout the genome. This work resulted in identification of a number of candidate regions that show association with response to one or more drugs. This renewal application capitalizes on these findings. We propose to (1) identify candidate genes and alleles that influence drug response using comparative sequencing and fine-scale association mapping, (2) use rapid transfection approaches to confirm which of the candidate genes identified are involved in resistance, and (3) examine whether specific alleles in these genes can predict drug treatment failure using clinical samples collected from patients in Thailand. Relevance of this research to public health. Malaria kills over one million people each year. The mainstay of malaria control is drug treatment, but treatment options are rapidly running out due to the evolution of resistance. We aim to locate parasite genes underlying resistance. This will allow us to track the spread of resistance, to better understand how antimalarial drugs work, and to redesign drugs to restore their effectiveness.

抗药性是控制疟疾的主要障碍，抗药性的传播有所增加 近几十年来疟疾死亡率。鉴定影响药物反应的寄生虫基因将 提高我们监测耐药性传播的能力，提供工具，更好地了解 因此，我们必须考虑到现有的抗疟药物，并允许合理地重新设计现有的药物。在泰国，这个问题尤其严重， 对除青蒿素衍生物以外的所有类别的抗疟药物都有高度抗药性。在初始 在该项目的资助期间，我们测量了来自一个单一的825个寄生虫分离株对八种药物的反应。 泰国-缅甸边境的一家诊所，然后使用426个双核苷酸对323个单克隆寄生虫进行基因分型。 微卫星标记在整个基因组中以50 kb（~3cM）间隔分布。这项工作导致 识别显示与对一种或多种药物的响应相关的多个候选区域。 此更新应用程序利用了这些发现。我们建议（1）确定候选基因， 使用比较测序和精细尺度关联映射影响药物反应的等位基因，（2） 使用快速转染方法来确认哪些候选基因参与了 耐药性，以及（3）检查这些基因中的特定等位基因是否可以预测药物治疗失败， 从泰国患者身上采集的临床样本。 这项研究与公共卫生的相关性。疟疾每年夺去100多万人的生命。主体 控制疟疾的最有效手段是药物治疗，但由于疟疾的发展， 阻力我们的目标是找到寄生虫抵抗力的基因。这将使我们能够追踪 耐药性，以更好地了解抗疟药物的作用机制，并重新设计药物以恢复其耐药性 有效性