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BIOGRAPHY:
Dr. McConville is Associate Professor of the Department of Biochemistry and Molecular Biology at the University of Melbourne. Dr. McConville received his Ph.D. in 1985 from the University of Melbourne in the field of biochemistry. He did postdoctoral research in the Immunoparasitology Department of the Walter and Eliza Hall Institute of Medical Research, and in the Biochemistry Department at Dundee University. In 1994 he received an Australian Senior Research Fellowship from the Wellcome Trust, and in 1999 and again in 2004 the National Health and Medical Research Council named him Principal Research Fellow. His HHMI project is to study metabolic pathways in pathogenic protozoa and mycobacteria.
RESEARCH ABSTRACT SUMMARY:
Identification of New Metabolic Pathways in Parasitic Protozoa
Parasitic protozoa are the cause of a number of important human
diseases, including malaria, African sleeping sickness, Chagas disease,
and leishmaniasis. To date, there are no well-defined subunit vaccines
against any of these diseases, and existing drug therapies suffer from
low efficacy, high toxicity, expense, and/or widespread drug
resistance. To identify new drug targets, there is a need to identify
parasite metabolic pathways that are important for the virulence and
survival of these pathogens in the mammalian host. With the
sequencing of several parasite genomes, multiparallel analysis of mRNA
(DNA arrays) and proteins (proteomics) has been used to model
metabolism in some parasitic protozoa. However, these analyses are
limited by the finding that a major fraction of all the predicted open
reading frames (ORFs) in the parasite genomes have no assigned function
and the difficulty of predicting how changes in mRNA or protein are
translated into changes in biological function. To identify
developmentally regulated and/or novel metabolic pathways, we undertook
an unbiased analysis of all primary and secondary metabolites in
different developmental stages of Leishmania (the model organism
for these studies). Metabolites were sequentially extracted in
aqueous-organic solvent mixtures and then analyzed by gas
chromatography (GC)/liquid chromatography (LC)/mass spectrometry. These
metabolomic analyses revealed 1) that several metabolic pathways are
highly up-regulated when leishmanial insect developmental stages invade
mammalian host cells and 2) the presence of new or previously
overlooked metabolic pathways. This approach led to the discovery of a
novel family of intracellular oligosaccharides that accumulate in the
intracellular amastigote stage and appear to be part of the parasite
stress response. The pathway leading to the biosynthesis of these
oligosaccharides has been partially characterized and may be a target
for new anti-parasite drugs.
Photo: Kent Kallberg, Kallberg Studios
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