Molecular Mechanisms of Artemisinin Resistance

项目总结 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 因此，最近在东南亚出现的青蒿素耐药性和潜在的传播， 多药耐药恶性疟原虫的震中引起了全球的关注。沙门氏菌临床分离株的研究 柬埔寨西部和转基因实验室菌株已经确定了青蒿素的因果联系 K13基因突变的抗性(Pf3D7_1343700)及其分子机制 青蒿素耐药性尚不清楚。东南亚寄生虫的种群遗传学研究表明 K13突变体在多种寄生虫种群中的独立出现。为了进一步解决这一紧急情况 问题是，这个美国-中国联合项目将(1)发现与青蒿素相关的新的分子标记 恶性疟原虫中国分离株全基因组联合抗性研究 缅甸边境地区，青蒿素家族药物部署历史最长的地区；(2)表演 功能研究，以确定K13基因及其多态在青蒿素耐药性中的作用；以及 (3)通过分子鉴定，阐明青蒿素抗性的分子机制。 K13蛋白的复合体。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的专业知识和资源。建议数 研究将利用从以下地点收集的大量适应培养的恶性疟原虫临床分离株 中国-缅甸边境地区以及我们早先在这一领域取得的重大进展 合作。这项研究产生的信息将对监测、遏制和威慑非常有用 青蒿素耐药性的传播，并将对区域和全球疟疾产生深远影响 淘汰赛。

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.