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菌株对新的病毒具有不同的抗药性。 抗疟疾药。创始人事件导致对传统抗疟疾药物的临床耐药性是罕见的，然而， 当它们发生时，它们发生在世界的特定区域，如东南亚(泰国)、中部 美洲(哥伦比亚)和巴布亚新几内亚。项目总监(PD)的实验室已经表明， 在体外获得对新抗疟疾药物的耐药性与起源于以下国家的寄生虫菌株最相关 抗药性很强。然而，这些研究是在实验室寄生虫克隆的情况下进行的 二十年前的文化。在各个研究实验室有着悠久的、不同的历史。 项目2的目标是确定南亚的寄生虫是否能够获得对实验性寄生虫的抵抗力 疟疾以超乎寻常的速度传播，并确定它们的基因类型。这里有一个独特的机会来 研究与寄生虫耐药性相关的复杂多态的起源，两者都是因为邻近 从南亚到缅甸和柬埔寨，并由于在确定的消除疟疾方面的一些重大倡议 印度的一些地区。 在这个项目中，将对南亚性行为者中现存的和新分离的恶性疟原虫进行表型分析。 基于获得能力的多重药物(或ARMD)加速耐药特性 通过体外选择实验对新的、特征良好的抗疟药产生抗药性。方法论 因为在体外，PD的实验室已经开发出了选择素，并且已经得到了很好的证实。使用3种不同的化学物质 对于探针，寄生虫将根据抗性频率、点突变率、 而扩增/缺失事件发生的频率相同和不同的抗性机制将是 来自世界各地的已建立的实验室克隆与来自中国的新的培养适应的野外菌株的比较 南亚。