Molecular Mechanisms of Artemisinin Resistance

项目摘要 以青蒿素为基础的联合疗法是治疗恶性疟原虫最有效的一线疗法 疟疾;因此，最近在东南亚出现和潜在的青蒿素耐药性， 多重耐药恶性疟原虫的中心，引起了全球的关注。临床分离株的研究 柬埔寨西部和转基因实验室菌株已经建立了青蒿素的因果关系 K13基因突变（Pf3D7_1343700）的耐药性，但K13介导的耐药的分子机制 青蒿素耐药性尚不清楚。对东南亚寄生虫的群体遗传学研究表明， K13突变体在多个寄生虫种群中独立出现。为进一步解决这一紧迫问题， 问题是，美国-中国联合项目将（1）鉴定与青蒿素相关的新分子标记 通过对来自中国的恶性疟原虫分离株的全基因组关联研究， 缅甸边境地区，青蒿素类药物部署历史最长;（2）执行 功能研究，以确定K13基因及其多态性在青蒿素耐药性中的作用; (3)通过对青蒿素抗性分子的鉴定，阐明青蒿素抗性的分子机制， K13蛋白的复合物。这个联合项目建立在我们过去合作的坚实基础上， 包括来自合作机构的互补专业知识和资源。拟议 这些研究将利用大量的培养适应性恶性疟原虫临床分离株档案，这些分离株是从 中缅边境地区，以及我们在这一领域从早期的 合作。这项研究所产生的信息将非常有助于监测、遏制和威慑 这将对区域和全球疟疾产生深远影响 消除运动。

PROJECT SUMMARY Artemisinin-based combination therapies are the most effective frontline treatments for Plasmodium falciparum malaria; therefore, the recent emergence and potential spread of artemisinin resistance in Southeast Asia, the epicenter of multidrug-resistant P. falciparum, has raised global concerns. Studies of clinical isolates from western Cambodia and genetically modified laboratory strains have established a causal link of artemisinin resistance with mutations in the K13 gene (Pf3D7_1343700), but the molecular mechanism of K13-mediated artemisinin resistance is not understood. Population genetic studies of parasites from Southeast Asia showed independent emergence of the K13 mutants in multiple parasite populations. To further address this urgent problem, this U.S.-China joint project will (1) identify novel molecular markers associated with artemisinin resistance through a genome-wide association study of P. falciparum parasite isolates from the China- Myanmar border area, where artemisinin family drugs have the longest history of deployment; (2) perform functional studies to determine the role of the K13 gene and its polymorphisms in artemisinin resistance; and (3) elucidate the molecular mechanism of artemisinin resistance through the identification of the molecular complex of the K13 protein. This joint project, built on a solid foundation of our past collaboration, encompasses the complementary expertise and resources from the collaborating institutions. The proposed studies will take advantage of the large archive of culture-adapted P. falciparum clinical isolates collected from the China-Myanmar border area and the significant inroad we have made into this field from our earlier collaborations. Information generated from this study will be highly useful for monitoring, curbing and deterring the spread of artemisinin resistance, and will have far-reaching impacts on both regional and global malaria elimination campaigns.