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    Investigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium falciparum

    Cover for Investigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium falciparum
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    View/Open: Gaviria_georgetown_0076D_12310.pdf (4.2MB) Bookview

    Creator
    Gaviria, David Alejandro
    Advisor
    Roepe, Paul D
    Metallo, Steven J
    Abstract
    By 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.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/558234
    Date Published
    2013
    Subject
    Biochemistry; Parasitology; Biochemistry; Parasitology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    218 leaves
    Collections
    • Graduate Theses and Dissertations - Chemistry
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      Gorka, Alexander Patrick (Georgetown University, 2013)
      Efficacy of, mechanisms of action of, and resistance to chemotherapeutic agents targeted against the malarial parasite Plasmodium falciparum have historically been defined by quantifying cytostatic potency or growth-inhibition. ...
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility