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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI054518-03
Application #
6933942
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Coyne, Philip Edward
Project Start
2003-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$124,524
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Sarr, Ousmane; Ahouidi, Ambroise D; Ly, Omar et al. (2008) Mutations in PFCRT K76T do not correlate with sulfadoxine-pyrimethamine-amodiaquine failure in Pikine, Senegal. Parasitol Res 103:765-9
Daily, J P; Scanfeld, D; Pochet, N et al. (2007) Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 450:1091-5
Volkman, Sarah K; Sabeti, Pardis C; DeCaprio, David et al. (2007) A genome-wide map of diversity in Plasmodium falciparum. Nat Genet 39:113-9
Ndiaye, D; Daily, J P; Sarr, O et al. (2006) Defining the origin of Plasmodium falciparum resistant dhfr isolates in Senegal. Acta Trop 99:106-11
Ndiaye, D; Daily, J P; Sarr, O et al. (2005) Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in Senegal. Trop Med Int Health 10:1176-9
Daily, Johanna P; Le Roch, Karine G; Sarr, Ousmane et al. (2005) In vivo transcriptome of Plasmodium falciparum reveals overexpression of transcripts that encode surface proteins. J Infect Dis 191:1196-203
Sarr, Ousmane; Myrick, Alissa; Daily, Johanna et al. (2005) In vivo and in vitro analysis of chloroquine resistance in Plasmodium falciparum isolates from Senegal. Parasitol Res 97:136-40
Daily, J P; Roberts, C; Thomas, S M et al. (2003) Prevalence of Plasmodium falciparum pfcrt polymorphisms and in vitro chloroquine sensitivity in Senegal. Parasitology 126:401-5