Molecular Mechanisms of Artemisinin Resistance

青蒿素耐药的分子机制

基本信息

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
项目类别：
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

项目摘要

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，青蒿素类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

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
作者：
通讯作者：

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.