E. coli that produce heat-stable enterotoxin (ST) are a major cause of infant morbidity and mortality due to diarrheal disease in underdeveloped nations. ST-mediated diarrhea is also a significant health problem in the U.S., since it is a major cause of Traveller's diarrhea. This application seeks to continue the supervised research experience of the applicant in studying the mechanisms by which the host turns off ST-induced secretion and to begin the supervised research experience of the applicant in studying the molecular biology of the ST receptor. The long-term goal of this application is to better understand the ST-enterocyte interaction and thereby help to design effective treatment strategies for ST-induced diarrhea. As a logical extension of the applicant's previous work on the binding of ST to rat and human small intestine and colon, this application proposes three specific aims: 1) to study the regulation of ST-induced secretion by toxin inactivation in the rat and human, 2) to identify, isolate and characterize the ST receptor in human intestine and 3) to clone a cDNA probe for the human ST receptor and study the abundance of mRNA for this receptor as a function of development. To accomplish this first aim, the proposed work will characterize the rate, degree and nature of intestinal inactivation of ST using various assays including high performance liquid chromatography, brush border membrane binding assay, guanylate cyclase assay, suckling mouse assay and enzyme linked immunoadsorbant assay. To accomplish the second aim, the applicant proposes to generate monospecific anti-ST receptor antibodies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes and Digestive and Kidney Diseases Special Grants Review Committee (DDK)
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Cincinnati Children's Hospital Medical Center
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Cohen, M B; Witte, D P; Hawkins, J A et al. (1995) Immunohistochemical localization of guanylin in the rat small intestine and colon. Biochem Biophys Res Commun 209:803-8
Sciaky, D; Kosiba, J L; Cohen, M B (1994) Genomic sequence of the murine guanylin gene. Genomics 24:583-7
Laney Jr, D W; Bezerra, J A; Kosiba, J L et al. (1994) Upregulation of Escherichia coli heat-stable enterotoxin receptor in regenerating rat liver. Am J Physiol 266:G899-906
Cohen, M B; Jensen, N J; Hawkins, J A et al. (1993) Receptors for Escherichia coli heat stable enterotoxin in human intestine and in a human intestinal cell line (Caco-2). J Cell Physiol 156:138-44
Mann, E A; Cohen, M B; Giannella, R A (1993) Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells. Am J Physiol 264:G172-8
Cohen, M B; Hawkins, J A; Weckbach, L S et al. (1993) Colonization by enteroaggregative Escherichia coli in travelers with and without diarrhea. J Clin Microbiol 31:351-3
Lewis, L G; Witte, D P; Laney, D W et al. (1993) Guanylin mRNA is expressed in villous enterocytes of the rat small intestine and superficial epithelia of the rat colon. Biochem Biophys Res Commun 196:553-60
Cohen, M B; Giannella, R A (1992) Hemorrhagic colitis associated with Escherichia coli O157:H7. Adv Intern Med 37:173-95
Mezoff, A G; Giannella, R A; Eade, M N et al. (1992) Escherichia coli enterotoxin (STa) binds to receptors, stimulates guanyl cyclase, and impairs absorption in rat colon. Gastroenterology 102:816-22
Cohen, M B; Giannella, R A (1992) Jejunal toxin inactivation regulates susceptibility of the immature rat to STa. Gastroenterology 102:1988-96

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