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Research | HASLAM LAB
Dr. Haslam's laboratory is investigating how
bacterial toxins damage human cells and why humans are susceptible
to diseases caused by these toxins. Most of these studies are
focused on shiga toxin, the agent responsible for hemolytic uremic
syndrome in children. This toxin is released by strains of E. coli
that commonly colonize domestic animals, and consequently is often
associated with food-borne outbreaks. Dr. Haslam's laboratory has
found than most animals are resistant to the toxin because they
produce an enzyme called Forssman synthetase. This enzyme modifies
toxin receptors, making them unavailable for toxin binding.
Humans, however, are unable to make this enzyme and consequently
have numerous toxin receptors available.
After binding to receptors at the surface of
human cells, shiga toxin is transported through the cell via a
novel retrograde pathway. The ultimate destination for shiga toxin
is the cytoplasm, where it inactivates ribosomes, inhibits protein
synthesis, and induces cell death. Dr. Haslam's laboratory
recently identified a molecular chaperone that is utilized by
shiga toxin to gain access to the cytoplasm. The laboratory is
currently investigating the function of this chaperone both in
toxin trafficking and in normal cellular biology. It is hoped that
by understanding how toxin molecules bind to human cells and find
their way to the cytoplasm, treatments may be directed against
these steps in toxin-mediated diseases.
In a separate project we are investigating the intracellular
trafficking of shiga toxin within host cells. Using a genetic
screen for molecules involved in toxin trafficking, we isolated
the cDNA for a novel ER-localized chaperone, which we named HEDJ.
We found that shiga toxin is capable of transport across the ER
membrane after interaction with HEDJ. Apparently, shiga toxin
"pretends" to be a misfolded host protein in order to exploit HEDJ
and and the "ER quality-control pathway" to gain access to the
cytoplasm. We are currently investigating the role of HEDJ and
other chaperones in normal cellular biology as well as toxin
trafficking.
Contact Information
office phone: 314-286-2888
office fax: 314-286-2895
lab phone: 314-286-2875 office location:
Room 6108, McDonnell Pediatric Research Building mailing address:
Department of Pediatrics
Washington University School of Medicine
660 South Euclid Ave., Campus Box 8208
St. Louis, MO 63110 shipping address:
Washington University School of Medicine
Dept of Pediatrics
MPRB 6th floor
4938 Parkview Place
St. Louis, MO 63110
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SCHOOL OF MEDICINE
