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dc.contributor.authorValderramos, Stephanie Lina Gaw
dc.date.accessioned2018-07-12T17:35:25Z
dc.date.available2018-07-12T17:35:25Z
dc.date.issued2009
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1474.;Advisors: David A. Fidock.
dc.identifier.urihttp://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3351411
dc.identifier.urihttps://hdl.handle.net/20.500.12202/1028
dc.description.abstractThe appearance and spread of chloroquine (CQ) resistance in Plasmodium falciparum has had a devastating impact on the treatment and control of malaria. The key determinant of CQ resistance is PfCRT (P. falciparum chloroquine resistance transporter), and genetic studies have demonstrated that PfCRT mutations were sufficient to confer CQ resistance to a CQ-sensitive clone, and the PfCRT K76T mutation was essential for CQ resistance. Although clinical epidemiology studies have found the K76T mutation to be a highly sensitive marker of CQ resistance, some patients harboring mutant pfcrt parasites are cured by CQ treatment. This may be due to partial immunity, or other parasite genes are necessary to augment pfcrt-mediated CQ resistance. To test this hypothesis, we have engineered mutant pfcrt into various CQS lines. Introduction of the South American-type 7G8 mutant pfcrt allele conferred either tolerance or resistance to CQ, depending on the genetic background. These data suggest that in certain genetic backgrounds, other genes might be required in addition to mutant PfCRT to confer CQ resistance.;Another parasite transporter protein involved in resistance to antimalarial compounds is PfMDR1, the P. falciparum homologue of mammalian P-glycoprotein. Using allelic exchange techniques, we demonstrated that 3' mutations in pfmdr1 contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in two different genetic backgrounds. In a parallel study, we genetically reduced pfmdr1 copy number in a parasite strain carrying two copies of this gene, and confirmed the role of pfmdr1 expression levels in mediating mefloquine resistance, as well as increased sensitivity to quinine, halofantrine, lumefantrine, and artemisinins.;Alternative treatments for drug resistant malaria are artemisinin-based combination therapies (ACT). The mechanism of artemisinin action in P. falciparum remains unknown, and one candidate target is the malarial SERCA ortholog PfATP6. Artemisinin was shown to specifically inhibit PfATP6 activity in Xenopus oocytes, and an L263E mutation completely abolished this inhibition. To determine whether this single amino acid change at L263 could render the parasite resistant to artemisinin, we introduced the L263E mutation into P. falciparum. We found that the L263E mutation is insufficient to confer resistance to artemisinin compounds in the malaria parasite.
dc.publisherProQuest Dissertations & Theses
dc.subjectMicrobiology.
dc.subjectParasitology.
dc.subjectPharmacology.
dc.titleInvestigations into the genetic basis of Plasmodium falciparum resistance to antimalarial drugs
dc.typeDissertation


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