Cystic fibrosis (CF), the most common semilethal hereditary disease among Caucasians, is manifest as a generalized dysfunction of exocrine glands. Mucous secretions throughout the body are abnormal in CF, but the subcellar defect underlying this abnormality is not understood. My goals are to determine first whether intestinal gylcoprotein-secreting cells of CF patients respond to extracellular secretagogues and inhibitors in the same way as do their counterparts in normal individuals, and second, whether CF mucous cells, when stimulated to secrete, carry out exocytosis in a normal fashion. Glycoprotein transport and secretion in rectal goblet and columnar cells will be studied in laboratory animals and in human rectal biopsies, both normal and CF, maintained in organ culture. The effects of various neurotransmitters, GI hormones and amines on the intracellular movement and release of radioactively labeled mucous glycoproteins will be assessed by autoradiography. The interaction, fusion and fission of intracellular membranes which accompany acceleration of exocytosis in goblet cells will be investigated in detail by freeze-fracture and electron microscopy. My freeze-fracture studies on human rectal goblet cells revealed the presence of uniquely extensive and long-lived membrane interactions in these cells. Under conditions of secretory stimulation, these interaction sites break down in an orderly sequence. Through systematic comparison of autoradiographic, freeze-fracture and ultrastructural data from normal and CF mucous cells, I hope to establish whether the CF genetic defect leads to alterations in the regulation of secretion or in the membranes involved in exocytosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Giannasca, K T; Giannasca, P J; Neutra, M R (1996) Adherence of Salmonella typhimurium to Caco-2 cells: identification of a glycoconjugate receptor. Infect Immun 64:135-45
Zhou, F; Kraehenbuhl, J P; Neutra, M R (1995) Mucosal IgA response to rectally administered antigen formulated in IgA-coated liposomes. Vaccine 13:637-44
Trahair, J F; Wilson, J M; Neutra, M R (1995) Identification of a marker antigen for the endocytic stage of intestinal development in rat, sheep, and human. J Pediatr Gastroenterol Nutr 21:277-87
Michetti, P; Porta, N; Mahan, M J et al. (1994) Monoclonal immunoglobulin A prevents adherence and invasion of polarized epithelial cell monolayers by Salmonella typhimurium. Gastroenterology 107:915-23
Pakkanen, R; Neutra, M (1994) Bovine colostrum ultrafiltrate: an effective supplement for the culture of mouse-mouse hybridoma cells. J Immunol Methods 169:63-71
Giannasca, P J; Giannasca, K T; Falk, P et al. (1994) Regional differences in glycoconjugates of intestinal M cells in mice: potential targets for mucosal vaccines. Am J Physiol 267:G1108-21
Amerongen, H M; Wilson, G A; Fields, B N et al. (1994) Proteolytic processing of reovirus is required for adherence to intestinal M cells. J Virol 68:8428-32
Neutra, M R; Kraehenbuhl, J P (1994) Mucosal immunization via M cells for production of protective secretory IgA antibodies. Am J Trop Med Hyg 50:10-3
Reinhart, F D; Phillips, T E; Trahair, J F et al. (1994) Identification of R-GRAMP, a membrane glycoprotein of regulated secretory granules in primate cells. Eur J Cell Biol 64:243-56
Apter, F M; Lencer, W I; Finkelstein, R A et al. (1993) Monoclonal immunoglobulin A antibodies directed against cholera toxin prevent the toxin-induced chloride secretory response and block toxin binding to intestinal epithelial cells in vitro. Infect Immun 61:5271-8

Showing the most recent 10 out of 22 publications