June Sherie Almenoff
Consulting Professor in the Department of Medicine
Infection with enterotoxigenic E. coli is an important world health problem. It is a leading cause of infant mortality in developing countries, and a common agent of travelers' diarrhea. Many pathogenic ETEC strains cause disease by elaboration of heart-stable enterotoxin (ST), a small peptide that binds to specific intestinals receptors. The receptor for ST is a unique transmembrane guanylyl cyclase (GC-C) that is activated in response to toxin binding. The goals of this laboratory are to identify molecular and cellular mechanisms that regulate the host response to toxin. The following projects, which intergrate pharmacologic, cellular, and molecular biologic techniques are ongoing in our laboratory:
1) Characterization of the oligomeric interactions of the receptor, and elucidation of their role in toxin mediated receptor activation. We have engineered dominant negative mutants that have permitted us to elucidate the receptor's novel mode of activation.
2) Elucidation of the mechanisms by which a negative regulatory domain regulates signalling. We have demonstrated that a kinaselike domain within the receptor acts as an autoinhibitor domain.
3) Examination of post-translational processing events modulate receptor signalling. We have preliminary data demonstrating that the receptor exists in multiple forms in vivo. We are currently elucidating where in the cells these different forms are generated, and how they interact with toxin.
4) To characteize the cellular response of receptors to prolonged toxin stimulation: We have preliminary data demonstrating that the receptor undergoes toxin-mediated desensitization, and are currently characterizing these mechanisms.
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