Drug resistance in Plasmodium falciparum

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.