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Cover for Investigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium falciparum
dc.contributor.advisorRoepe, Paul Den
dc.contributor.advisorMetallo, Steven Jen
dc.creatoren
dc.date.accessioned2013-06-07T19:27:23Zen
dc.date.available2013-06-07T19:27:23Zen
dc.date.created2013en
dc.date.issueden
dc.date.submitted01/01/2013en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_558234.tar;APT-ETAG: e1bd0303068293a12b3c505184293059en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractBy quantifying antimalarial cytocidal activities (measured as LD50s) and comparing them to cytostatic activities (measured as IC50s), Paguio et al., 2011 showed a clear difference between some drug activities at different drug levels. This work showed that fold-resistance ratios are dramatically different at cytostatic vs. cytocidal drug levels as are multidrug resistance (MDR) patterns and verapamil (VPL) chemoreversal. These observations provide a fertile ground for research in elucidating drug targets and mechanisms at cytocidal levels. Ghosh et al., 2012 elucidated an autophagy pathway involved in mitochondrial degradation in response to starvation in T. gondii, the organism most closely related to human malaria parasites outside of other Plasmodium species. Sequence analyses of the autophagy-related (Atg) proteins found in T. gondii reveal close homologues in P. falciparum. Atg protein homologues involved in every step of the canonical autophagy pathway were found. Vps34 (the catalytic subunit of the kinase complex responsible for phagophore nucleation) is highly homologous within conserved domains, though it is much larger due to repetitive sequences that exist between putative helical regions. Since chloroquine (CQ) is an established inhibitor of autophagy and autophagy appears to be a functional system in malaria parasites, I have investigated the function of this pathway in malaria parasites and any possible connections to CQ resistance (CQR). This work has produced important insights into the poorly understood role of Atg proteins in malaria parasites, their regulation, and signaling pathways. Importantly, the data contained in this work suggest a relationship between autophagy and resistance to CQ. Moreover, differences between CQ sensitive (CQS) and CQR parasites suggest that Ca2+ transients may also play a role in resistance.en
dc.formatPDFen
dc.format.extent218 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceChemistryen
dc.subject.lcshBiochemistryen
dc.subject.lcshParasitologyen
dc.subject.otherBiochemistryen
dc.subject.otherParasitologyen
dc.titleInvestigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium falciparumen
dc.typethesisen


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