Drug resistance in Plasmodium falciparum

恶性疟原虫的耐药性

• 批准号: 6933942
• 负责人: Johanna Patricia Daily
• 金额: $ 12.45万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933942
• 关键词: Plasmodium berghei; Plasmodium falciparum; chloroquine; clinical research; drug resistance; emerging infectious disease; gene expression; genetic polymorphism; genetic transcription; human subject; immunogenetics; laboratory rat; malaria; microarray technology; patient oriented research; polymerase chain reaction; serial analysis of gene expression

DESCRIPTION (provided by applicant): Malaria continues to have a major impact on global health with rates of 1-3 million deaths annually. In addition, the high prevalence of chloroquine resistant Plasmodium falciparum, has contributed to the rising morbidity and mortality in Africa. Discovery of genetic correlates of chloroquine resistance would not only provide a marker for epidemiologic studies but would guide studies to characterize the molecular basis of resistance. A major advance toward this goal was the recent identification of a mutation in pfcrt, that is consistently found in chloroquine resistant parasites. Importantly, this mutation can be found in chloroquine sensitive isolates, which suggest that this mutation is required, but that there are other genetic loci that contribute to the resistance phenotype. Two major approaches to identify the other genes involved in chloroquine resistance are proposed. The first approach will examine the correlation of additional DNA polymorphisms found in pfmdr1 and novel genes, with chloroquine resistance through field based studies. Drug resistance can also be mediated by alterations in transcription level, a mechanism that cannot be detected by analysis of single point mutations. Therefore a second and complementary approach will compare transcriptional profiles between chloroquine sensitive and resistant parasites. Functional studies of genes identified by either method will be conducted in an animal model system. The long term goal of this proposal is 1) to fully characterize the genetic basis of chloroquine resistance through integration of field observations and standard and innovative laboratory methods 2) provide the investigator with the additional necessary complementary skills of clinical research and molecular methods to develop into an independent investigator in malaria.

描述(申请人提供)：疟疾继续对全球健康产生重大影响，每年有100-300万人死亡。此外，抗氯喹恶性疟原虫的高流行也是非洲发病率和死亡率上升的原因之一。氯喹耐药性遗传相关性的发现不仅将为流行病学研究提供标记，而且将指导研究表征耐药性的分子基础。朝着这一目标迈进的一个重大进展是最近发现了pfcrt的一个突变，这种突变一直存在于抗氯喹寄生虫中。重要的是，这种突变可以在氯喹敏感菌株中发现，这表明这种突变是必需的，但还有其他遗传位点与抗药性表型有关。提出了两种主要的方法来鉴定与氯喹抗性有关的其他基因。第一种方法将通过基于现场的研究，检查在pfmdr1和新基因中发现的其他DNA多态与氯喹抗性的相关性。耐药也可以通过转录水平的变化来调节，这是一种通过分析单点突变无法检测到的机制。因此，第二种互补的方法将比较氯喹敏感和耐药寄生虫之间的转录图谱。任何一种方法确定的基因的功能研究都将在动物模型系统中进行。 这项建议的长期目标是1)通过整合现场观察和标准和创新的实验室方法，充分确定氯喹耐药性的遗传基础；2)为研究人员提供额外的必要补充技能，包括临床研究和分子方法，以发展成为疟疾的独立研究人员。