Molecular Mechanisms of Artemisinin Resistance

青蒿素耐药的分子机制

• 批准号: 10062860
• 负责人: LIWANG CUI
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-13 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062860
• 关键词: 1-Phosphatidylinositol 3-Kinase; Achievement; Address; Affect; Affinity Chromatography; Agreement; Archives; Area; Artemisinins; Binding; Biological Assay; CRISPR/Cas technology; Cambodia; Cellular Stress; Chemistry; China; Clinical; Collaborations; Collection; Combined Modality Therapy; Complex; Containment; Development; Evolution; Falciparum Malaria; Family; Foundations; Genes; Genetic; Genetic Polymorphism; Genetic Population Study; Genomics; Genotype; Half-Life; In Vitro; Institution; Joints; Laboratories; Link; Malaria; Mass Spectrum Analysis; Measures; Mediating; Molecular; Monitor; Morbidity - disease rate; Multi-Drug Resistance; Mutation; Myanmar; Normal Range; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Play; Population; Predisposing Factor; Proteins; Recording of previous events; Resistance; Resources; Role; SYBR Green I; Signal Pathway; Solid; Southeastern Asia; System; Technology; Tertiary Protein Structure; Ubiquitin; Up-Regulation; Work; analog; aptamer; artemether; artesunate; base; biological adaptation to stress; design; genetic manipulation; genome analysis; genome editing; genome wide association study; genome-wide analysis; knock-down; molecular marker; mortality; multicatalytic endopeptidase complex; mutant; novel; parasite genome; protein complex; resistance gene; resistance mechanism; resistant Plasmodium falciparum; response; tool; transcriptome; yeast two hybrid system

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.

项目摘要 基于青蒿素的组合疗法是恶性疟原虫的最有效的前线疗法 疟疾;因此，最近在东南亚的青蒿素抵抗的出现和潜在传播， 多药耐药性恶性疟原虫的中心引起了全球关注。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基因中突变的抗性（PF3D7_1343700），但K13介导的分子机制 青蒿素耐药性尚不清楚。东南亚寄生虫的人口遗传研究表明 K13突变体在多个寄生虫种群中的独立出现。进一步解决这一紧急情况 问题，这个美国 - 中国联合项目将（1）确定与青蒿素相关的新型分子标记 通过全基因组寄生虫分离株从中国 - 缅甸边境地区，阿耳震蛋白家庭药物的部署历史最长； （2）执行 确定K13基因及其多态性在青蒿素抗性中的作用的功能研究；和 （3）通过鉴定分子来阐明青蒿素耐药性的分子机制 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， 包括合作机构的补充专业知识和资源。提议 研究将利用从从中收集的大量培养物适应于培养的恶性疟原虫临床分离株 中国 - 孟买边境地区以及我们从早期开始进入这一领域的大量侵害 协作。从这项研究产生的信息将对监视，遏制和阻止非常有用 青蒿素抵抗的传播，将对区域和全球疟疾产生深远的影响 消除运动。

项目成果

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.

• DOI: 10.1016/j.ijpddr.2021.05.007
• 发表时间: 2021-08
• 期刊: International journal for parasitology. Drugs and drug resistance
• 作者: Siddiqui FA;Liang X;Cui L
• 通讯作者: Cui L

Characterization of the dual role of Plasmodium falciparum DNA methyltransferase in regulating transcription and translation.

• DOI: 10.1093/nar/gkad248
• 发表时间: 2023-05-08
• 期刊: Nucleic acids research
• 影响因子: 14.9

A type II protein arginine methyltransferase regulates merozoite invasion in Plasmodium falciparum.

• DOI: 10.1038/s42003-023-05038-z
• 发表时间: 2023-06-22
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Lucky, Amuza Byaruhanga;Wang, Chengqi;Liu, Min;Liang, Xiaoying;Min, Hui;Fan, Qi;Siddiqui, Faiza Amber;Adapa, Swamy Rakesh;Li, Xiaolian;Jiang, Rays H. Y.;Chen, Xiaoguang;Cui, Liwang;Miao, Jun
• 通讯作者: Miao, Jun

Fitness Loss under Amino Acid Starvation in Artemisinin-Resistant Plasmodium falciparum Isolates from Cambodia.

• DOI: 10.1038/s41598-018-30593-5
• 发表时间: 2018-08-22
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bunditvorapoom D;Kochakarn T;Kotanan N;Modchang C;Kümpornsin K;Loesbanluechai D;Krasae T;Cui L;Chotivanich K;White NJ;Wilairat P;Miotto O;Chookajorn T
• 通讯作者: Chookajorn T

A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum.

• DOI: 10.1371/journal.ppat.1009351
• 发表时间: 2021-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Miao J;Wang C;Lucky AB;Liang X;Min H;Adapa SR;Jiang R;Kim K;Cui L
• 通讯作者: Cui L