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Collaborative studies, with funding by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), are focused on the physiological function of the transmembrane receptor guanylate cyclase-C (GC-C) and its ligands, guanylin and uroguanylin. We are currently centered on understanding how GC-C maintains effective barrier function in the intestine and regulates gene expression in intestinal epithelial cells. By utilizing transgenic animals that are engineered to lack GC-C, guanylin, or uroguanylin, we are determining the role that this guanylate cyclase system plays in susceptibility to intestinal injury, inflammation and infection.
PIs: Steinbrecher and Cohen
Our goal is to understand how GSK-3β serves as a central
signal transduction node that integrates multiple inputs from the epithelial
cell surface to allow for a coordinated cellular response. We are specifically
interested in how GSK-3β regulates the activity and interaction of
transcription factors such as NF-κB, AP-1 and β-catenin. We have demonstrated
that GSK-3β is important for proper expression of genes associated with the
development of intestinal inflammation and cancer. By using both in vitro molecular techniques as well as
transgenic animal models, we hope to gain insight into the manner in which
GSK-3β and the transcription factors it controls cooperate to dictate the
development of inflammation and tumorigenesis of the intestine.
Phase 1 Study to Determine the Safety and Immunogenicity of an Oral ETEC Candidate Vaccine, Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli.
This study will assess the safety of dmLT vaccine when administered as a single oral dose over a range of dose levels in healthy adult subjects. Additional objectives are to evaluate the immunogenicity of a single oral dose of dmLT vaccine over a range of doses in healthy adult subjects. The study is being performed in collaboration with the University of Maryland through a subcontract from the Food and Waterborne Infection Network of NIAID.
Evaluations of safety, solicited symptoms / subject memory aid and laboratory evaluations will be conducted. The immunogenicity outcome measures of interest are stimulation of anti-dmLT antibody secreting cells (ASC) measured by ELISPOT and seroconversion rates and geometric mean titers of serum anti-LT IgG and IgA antibodies measured by ELISA. This is a Phase 1 dose-escalation study with the planned doses of 5 μg, 25 μg, 50 μg and 100 μg.
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