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BIOGRAPHY:
Dr. Crabb is Senior Lecturer in the Department of Microbiology and
Immunology of the University of Melbourne in Australia. He received his
Ph.D. in the field of virology in 1992 from the University of
Melbourne, and did postdoctoral research in the Immunoparasitology Unit
of the Walter and Eliza Hall Institute of Medical Research. He received
the 1999 Young Tall Poppy Award given to 15 Australian scientists for
achievements in medical research and the 2002 Burnet Prize of the
Walter and Eliza Hall Institute of Medical Research. In 2003 he was
awarded a Senior Research Fellowship by the National Health and Medical
Research Council of Australia. With his HHMI award he will be
conducting functional studies on merozoite surface proteins of the
malaria parasite Plasmodium falciparum.
RESEARCH ABSTRACT SUMMARY:
A Telomere Position Effect is Involved in the Differential Expression of Subtelomeric Genes in Plasmodium falciparum
Antigenic variation and cytoadherence of infected erythrocytes play a major role in the development of severe disease and chronic infection in Plasmodium falciparum malaria. Both processes are mediated by the virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of infected red blood cells. PfEMP1 is encoded by the var gene family, comprising approximately 60 highly diverse members per parasite genome. Most var genes are located at chromosome ends, which are themselves attached to the nuclear periphery. In P. falciparum, mutually exclusive transcription of the var gene family ensures that only one copy is activated in a single parasite, whereas transcription of all other var members remains silenced. To investigate mechanisms mediating transcriptional silencing in P. falciparum subtelomeric regions, we generated a transgenic parasite line. Parasite growth under drug selection artificially activates transcription of the human dihydrofolate reductase (hdhfr) resistance gene introduced into the rep20 repeat region at one end of chromosome 3. In the absence of the drug, however, this locus is silenced, demonstrating a telomere position effect (TPE). We showed that the active and silenced transcriptional states of the hdhfr gene are associated with an altered chromatin structure in the upstream promoter. Moreover, fluorescent in situ hybridization (FISH) analysis of these parasites transfected with a second selectable marker present on episomes and targeted to the nuclear periphery suggests the presence of a physical expression site at the nuclear periphery that is permissive for transcription.
Photo: Kent Kallberg, Kallberg Studios
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