Parasite Plasticity in South Asian Malaria

南亚疟疾中的寄生虫可塑性

基本信息

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
项目类别：
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

项目摘要

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获得对新病毒的抗性的能力不同抗疟药。导致传统抗疟药产生临床耐药性的创始人事件很少见，但当它们发生时，它们发生在世界的特定地区，例如东南亚（泰国）、中部地区美洲（哥伦比亚）和巴布亚新几内亚。项目总监 (PD) 实验室已证明有能力在体外获得对新抗疟药的耐药性与原产于有疟疾国家的寄生虫菌株最相关。高水平的耐药性。然而，这些研究是用实验室寄生虫克隆进行的二十年前的文化。并在各个研究实验室中拥有悠久而多样的历史。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的抗性以惊人的速度进行抗疟药物的研究，并确定其基因型。这里有一个独特的机会研究与寄生虫抗性相关的复杂多态性的起源，这都是因为邻近性南亚到缅甸和柬埔寨，以及由于在特定地区根除疟疾的一些重大举措印度地区。在该项目中，将对来自南亚患者的现有和新分离的恶性疟原虫进行表型分析根据其获得多种药物的能力，加速对多种药物的耐药性（或 ARMD）特征通过体外选择实验对新型、特征明确的抗疟药产生耐药性。方法论体外选择的方法是在 PD 实验室中开发出来的，并且已经得到很好的建立。使用 3 种不同的化学品探针，寄生虫将在耐药频率、点突变率、以及扩增/缺失事件的频率耐药机制的异同比较来自世界各地的已建立的实验室克隆和来自新培养适应的野外菌株南亚。