Mapping Drug Resistance Genes in Plasmodium Falciparum

耐药性是控制疟疾的主要障碍，耐药性的传播有所增加 近几十年的疟疾死亡率。识别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，为更好地了解疟疾的作用模式提供工具 抗疟疾药物，并允许对现有药物进行合理的重新设计。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疾药物都有高度的耐药性。在最初 这个项目的资助期我们测量了825个寄生虫分离株对8种药物的反应 在泰国-缅甸边境的诊所，然后用426双核苷酸对323种单克隆寄生虫进行了基因分型 微卫星标记在整个基因组中以50kb(~3 cM)的间隔分布。这项工作的结果是 识别与对一种或多种药物的反应有关的多个候选区域。 此续订申请充分利用了这些调查结果。我们建议(1)确定候选基因和 用比较测序和精细关联作图研究影响药物反应的等位基因，(2) 使用快速转染法确认哪些已识别的候选基因与 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。每年有100多万人死于疟疾。中流砥柱 疟疾控制的关键是药物治疗，但由于疟疾的演变，治疗选择正在迅速耗尽。 抵抗。我们的目标是定位潜在的抗药性寄生虫基因。这将使我们能够跟踪病毒的传播 耐药性，以更好地了解抗疟疾药物的作用方式，并重新设计药物以恢复其 有效性。

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.