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.

项目概要 基于青蒿素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，近期青蒿素耐药性在东南亚的出现和潜在蔓延， 多重耐药性恶性疟原虫的中心，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建立青蒿素的因果关系 K13基因（Pf3D7_1343700）突变产生耐药性，但K13介导的分子机制 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，这个中美联合项目将 (1) 识别与青蒿素相关的新型分子标记 通过对来自中国的恶性疟原虫寄生虫分离株进行全基因组关联研究来确定耐药性 缅甸边境地区，青蒿素家族药物部署历史最悠久； (2)执行 确定K13基因及其多态性在青蒿素耐药性中的作用的功能研究；和 (3)通过分子鉴定阐明青蒿素耐药的分子机制 K13 蛋白复合物。这个联合项目建立在我们过去合作的坚实基础之上， 涵盖合作机构的互补专业知识和资源。拟议的 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 中缅边境地区以及我们在这一领域取得的重大进展 合作。这项研究产生的信息对于监测、遏制和威慑非常有用 青蒿素耐药性的蔓延，将对区域和全球疟疾产生深远影响 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