Parasite Plasticity in South Asian Malaria

南亚疟疾中的寄生虫可塑性

• 批准号: 8306807
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 24.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306807
• 关键词: Africa; Alleles; Antigens; Antimalarials; Area; Asia; Asians; B-Lymphocytes; Biological; Biological Assay; Cambodia; Central America; Chemicals; Chloroquine; Chloroquine resistance; Clinical; Complex; Controlled Study; Country; Data; Dihydroorotate Dehydrogenase Inhibitor; Dihydropteroate Synthase; Disease; Drug resistance; Epidemiology; Erythrocytes; Event; Evolution; Farnesyl Transferase Inhibitor; Frequencies; Gene Duplication; Gene Transfer; Genes; Genetic; Genetic Crosses; Genetic Polymorphism; Genome; Genomics; Genotype; Geographic Locations; Geography; Goals; Host Defense; Human; Immune; Immune response; Immunoglobulin Variable Region; In Vitro; India; Individual; Laboratories; Life Cycle Stages; Link; Linkage Disequilibrium; Liver; Malaria; Membrane Proteins; Methodology; Methods; Molecular; Mutagenesis; Mutation; Myanmar; Organ; Papua New Guinea; Parasites; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Point Mutation; Population; Prevalence; Price; Primates; Property; Recording of previous events; Research; Resistance; Resistance development; Risk; Running; Sampling; Severity of illness; Site; South Asian; Southeastern Asia; Sporozoites; Stretching; Systems Development; Testing; Thailand; Thymidylate Synthase Inhibitor; Time; Treatment Failure; Variant; Virulent; Walkers; Work; base; drug quality; genome wide association study; improved; interest; non-drug; novel; preference; pressure; programs; research study; resistance mechanism; sample collection; thymidylate synthase-dihydrofolate reductase; tool; trait; vector

Strains of P. falciparum from different regions ofthe worid have varying capacifies to acquire resistance to new antimalarials. Founder events leading to clinical drug resistance against tradifional antimalarials were rare, yet, when they occurred, they occurred in specific regions ofthe worid such as SoutheastAsia (Thailand), Central America (Columbia), and Papua New Guinea. The Project Director's (PD) lab has shown that the capacity to acquire resistance to new antimalarials in vitro is best related to parasite strains originating in countries with high level of drug resistance. However, these studies were performed with laboratory parasite clones adapted to culture two decades ago. and have long, varied histories in individual research labs. The goal of Project 2 is to determine if parasites in South Asia can acquire resistance to experimental anfimalarials at extraordinary rates, and to establish their genotypes. There is a unique opportunity here to study origins of complex polymorphisms associated with resistance in parasites, both because ofthe proximity of South Asia to Myanmar and Cambodia, and due to some major initiafives to eradicate malaria in defined regions of India. In this project, exisfing and newly isolated P. falciparum from South Asian pafients will be phenotyped for the Accelerated Resistance to Mulfiple Drugs (or ARMD) trait based on their capacities to acquire resistance to novel, well-characterized anfimalarials through in vitro selecfion experiments. The methodologies for in vitro selecfions were developed, and are well established, in the PD's lab. Using 3 different chemical probes, the parasites will be characterized with respect to frequencies of resistance, rates of point mutations, and frequency of amplification/deletion events Similarities and differences in resistance mechanisms will be compared between established lab clones from around the worid and newly culture-adapted field strains from South Asia.

来自世界不同地区的恶性疟原虫株对新的疟原虫有不同的获得抗性的能力。 抗疟药导致对传统抗疟药产生临床耐药性的创始事件很少见，然而， 当它们发生时，它们发生在世界的特定地区，如东南亚（泰国），中亚， 美洲（哥伦比亚）和巴布亚新几内亚。项目主管（PD）实验室已经表明， 体外获得对新抗疟药物的耐药性与源自 高水平的耐药性。然而，这些研究是在实验室寄生虫克隆适应的情况下进行的。 20年前的文化。在各个研究实验室里有着悠久而多样的历史。 项目2的目标是确定南亚的寄生虫是否可以获得对实验性 以惊人的速度感染疟疾，并建立他们的基因型。这是一个难得的机会 研究与寄生虫抗性相关的复杂多态性的起源， 由于一些主要的消除疟疾倡议， 印度的地区。 在这个项目中，从南亚患者中分离的和新分离的恶性疟原虫将被分型 加速耐药多重药物（或ARMD）性状的基础上，他们的能力，以获得 通过体外选择实验对新的、充分表征的抗疟药产生抗性。的方法 在PD的实验室中，开发了用于体外选择的方法，并且得到了很好的建立。使用3种不同的化学物质 探针时，寄生虫将根据抗性频率，点突变率， 和扩增/缺失事件的频率。 比较了来自世界各地的实验室克隆和新培养适应的野外菌株， 南亚