Molecular epidemiology of drug resistance and population genetic structure of Pla

Pla耐药分子流行病学及群体遗传结构

• 批准号: 8103139
• 负责人: Fangli Lu
• 金额: $ 5.03万
• 依托单位: SUN YAT-SEN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103139
• 关键词: Africa; Antimalarials; Attention; Biochemistry; Cessation of life; Characteristics; China; Chloroquine; Chloroquine resistance; Country; Data; Development; Dihydrofolate Reductase; Dihydropteroate Synthase; Drug resistance; Economic Development; Epidemiology; Evolution; Folic Acid Antagonists; Genes; Genetic Markers; Genetic Polymorphism; Genetic Population Study; Genetic Variation; Genotype; Geographic Distribution; Goals; Haplotypes; Health; Health Benefit; Human; In Vitro; Individual; Infection; Intervention; Island; Lead; Life; Longevity; Malaria; Measures; Methods; Microsatellite Repeats; Molecular; Molecular Epidemiology; Monitor; Morbidity - disease rate; Morphology; Mutation; Parasites; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Point Mutation; Policies; Population; Prevalence; Province; Public Health; Pyrimethamine; Pyrimethamine-Sulfadoxine; Relapse; Reporting; Research; Resistance; Risk; Single Nucleotide Polymorphism; Southeastern Asia; Structure; Sulfadoxine; Sulfadoxine-pyrimethamine resistance; Suspension substance; Suspensions; Variant; Vivax Malaria; base; combat; disorder control; geographic population; in vivo; population genetic structure; programs; public health priorities; resistance mutation; resistant strain; transmission process

DESCRIPTION (provided by applicant): Malaria remains a serious public health problem in China. In the subtropical Yunnan Province and the tropical Hainan Island of China, malaria has been the most endemic with high transmission of both Plasmodium falciparum and P. vivax. However, most of the attention in terms of research and interventions has been focused in Africa and Southeast Asia, very few studies of malaria in China have been conducted. Because of extensive use, chloroquine (CQ) has now lost its efficacy due to the emergence of resistant strains in most parts of the world. Meanwhile, suspension of the use of CQ has resulted in reappearance of CQ sensitivity. However, there were differences in the evolution of CQ resistance between parasites from Yunnan and Hainan, the exact mechanism needs to be investigated. Sulfadoxine-pyrimethamine (SP) targets the dhfr and dhps genes of P. falciparum, and point mutations that confer resistance have been widely reported worldwide. Documenting the identity and extent of SP resistance is also critical for policy decisions regarding antimalarial drugs. In addition, P. vivax causes a large burden of morbidity in the world including China but traditionally has been understudied. Based on these, our long-term goal of this proposal is 1) to identify single-nucleotide polymorphism (SNP) and characterize the geographic distribution of genetic diversity, population structure, and haplotype variability at drug resistant loci of P. falciparum from Yunnan and Hainan, China, 2) to examine the geographic population structure, levels of genetic diversity of P. vivax using microsatellite and SNP, and 3) to yield valuable information for making more effective malaria control policies in China. In the past several years we have developed the molecular methods to study the genetics, population diversity, and evolution of malaria parasites, and have done some preliminary studies on malaria field isolates from Yunnan and Hainan using genetic markers, thus enabling us to study the molecular epidemiology of these important malaria parasites in this proposal. The specific aims are to: 1. Determine genetic polymorphisms associated with CQ resistance (CQR) in P. falciparum field isolates from Yunnan and Hainan provinces, China. 2. Determine the point mutation prevalence in the dhfr (pyrimethamine drug resistance) and dhps (sulfadoxine drug resistance) genes associated with SP resistance in P. falciparum field isolates from Yunnan and Hainan provinces, China. 3. Assess the changes of P. vivax genotypes using pvcsp, pvmsp1, pvmsp3-1 genes, and microsatellite markers and determine the geographic structure and specific epidemiological characteristics of P. vivax transmission in Yunnan and Hainan, China. 1 PUBLIC HEALTH RELEVANCE: The project will be of significant benefit to public health programs aimed at identifying and combating drug-resistant malaria, and have the potential to benefit the health of a substantial proportion of the world's population. The data will provide valuable information for extending the life span of individual antimalarial drugs and developing more appropriate malaria control policies in China.

描述(申请人提供)：疟疾仍然是中国严重的公共卫生问题。在亚热带的云南省和热带的海南岛中国，疟疾一直是最流行的，恶性疟和间日疟都有很高的传播率。然而，在研究和干预方面的注意力大多集中在非洲和东南亚，对中国疟疾的研究很少。由于氯喹(CQ)的广泛使用，由于世界大部分地区出现耐药菌株，CQ现已失去效力。同时，CQ的暂停使用导致了CQ敏感性的重现。然而，云南和海南两地寄生虫对CQ的抗性进化存在差异，其确切机制有待进一步研究。磺胺多辛(SP)以恶性疟原虫dhfr和dhps基因为靶点，导致恶性疟原虫耐药的点突变在世界范围内被广泛报道。记录SP耐药性的特征和程度对于抗疟疾药物的政策决策也是至关重要的。此外，间日疟原虫在包括中国在内的世界范围内造成了很大的发病率负担，但传统上对其研究较少。在此基础上，我们提出的长期目标是：1)鉴定恶性疟原虫中国云南和海南耐药基因座的单核苷酸多态性，并研究其遗传多样性、种群结构和单倍型变异的地理分布；2)利用微卫星和单核苷酸多态性分析间日疟原虫的地理种群结构和遗传多样性水平；3)为中国制定更有效的疟疾防治政策提供有价值的信息。在过去的几年里，我们发展了分子方法来研究疟疾寄生虫的遗传学、种群多样性和进化，并利用遗传标记对云南和海南的疟疾田间分离株进行了初步研究，从而使我们能够在本提案中研究这些重要疟疾寄生虫的分子流行病学。本研究的具体目的是：1.确定云南、海南两省恶性疟原虫田间分离物中与CQ抗性相关的遗传多态性，中国。2.对云南、海南两省恶性疟原虫田间分离株中与SP耐药相关的DHFR和DHPS基因进行点突变检测，中国。3.利用pvcsp、pvmsp1、pvmsp3-1基因和微卫星标记评估间日疟原虫基因分型的变化，确定云南和海南间日疟原虫传播的地理结构和特异性流行病学特征，中国。1公共卫生相关性：该项目将对旨在识别和抗击抗药性疟疾的公共卫生项目产生重大益处，并有可能造福于世界上相当大一部分人口的健康。这些数据将为中国延长个体抗疟疾药物的使用寿命和制定更合适的疟疾控制政策提供有价值的信息。