Paneth cell, antimicrobial peptide, development, defensin
The goals of this research program are to define mechanisms of innate immunity in the mammalian intestinal epithelium, focusing almost exclusively on the biology of the Paneth cell. In the small intestine, these cells secrete very large granules into the lumen of the crypts of LieberkÃ²hn, and those granule constituents include many antimicrobial peptides. Among the Paneth cell secretory products are approximately 20 different a-defensins, also known as cryptdins, as well as additional peptides coded by related genes in this family. Paneth cells secrete granules when exposed to bacteria or bacterial antigens, and the majority of the bactericidal activity in the secretion is due to cryptdins. It is the central hypothesis of the lab that these molecules function as endogenous antibiotics that influence the microenvironment of the crypt. The hypothesis is being tested by two primary approaches. First, the mechanisms that regulate a-defensin biosynthesis in fully-differentiated and developing Paneth cells are being investigated, and second, the biological activities and mode(s) of action of individual mouse a-defensins are being determined.
Maemoto, A., Qu, X., Rosengren, K.J., Tanabe, H., Henschen-Edman, A., Craik, D.J., and Ouellette, A.J.: Functional analysis of the alpha-defensin disulfide array in mouse cryptdin-4. J. Biol. Chem., in press, 2004.
Tanabe, H., Qu, X., Weeks, C.S., Cummings, J.E., Kolusheva, S., Walsh, K.B., Jelinek, R., Vanderlick, T.K., Selsted, M.E., and Ouellette, A.J.: Structure-activity determinants in Paneth cell alpha-defensins: Loss-of-function in mouse cryptdin-4 by charge-reversal at arginine residue positions, J. Biol. Chem. 279: 11976-11983, 2004. http://www.jbc.org/cgi/reprint/279/12/11976.pdf
Tanabe, H., Yuan, J., Zaragoza, M.M., Dandekar, S., Henschen-Edman, A., Selsted, M.E., and Ouellette, A.J.: Paneth cell alpha-defensins from rhesus macaque small intestine. Infect. Immun., 72: 1470-1478, 2004. 2004. http://iai.asm.org/cgi/reprint/72/3/1470.pdf
Satchell, D.P., Sheynis, T., Shirafuji, Y., Kolusheva, S., Ouellette, A.J., and Jelinek, R.: Interactions of mouse Paneth cell alpha-defensins and alpha-defensin precursors with membranes: Prosegment inhibition of peptide association with biomimetic membranes. J. Biol. Chem. 278:13838-13846, 2003. http://www.jbc.org/cgi/reprint/278/16/13838.pdf
Shirafuji, Y., Tanabe, H., Satchell, D.P., Henschen-Edman, A., Wilson, C.L., Ouellette, A.J.: Structural determinants of procryptdin recognition and cleavage by matrix metalloproteinase-7. J. Biol. Chem, 278: 7910-7919, 2003. http://www.jbc.org/cgi/reprint/278/10/7910.pdf
Ayabe, T., Satchell, D.P., Pesendorfer, P., Tanabe, H.,
Wilson, C.L., Hagen, S.J., Ouellette, A.J.: Activation of
alpha-defensins in mouse intestinal Paneth cells, J. Biol.
Chem. 277:5219-5228, 2002
Ayabe, T., Wulff, H., Darmoul, D., Cahalan, M.D., Chandy, K.G., and Ouellette, A.J.: Modulation of mouse Paneth cell a-defensin secretion by mIKCa1, a Ca2+-activated,intermediate-conductance potassium channel, J. Biol. Chem. 277:3793-3800, 2002.
Ayabe, T., Satchell, D.P., Wilson, C.L., Parks, W.C., Selsted, M.E., Ouellette, A.J.: Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nature Immunol. 1:113-118, 2000. http://www.nature.com/cgi-taf/DynaPage.taf?file=/ni/journal/v1/n2/full/ni0800_113_fs.html&content_filetype=pdf
Wilson, C.L., Ouellette, A.J., Satchell, D.P., Ayabe, T., López-Boado, Y.S., Stratman, J.L., Hultgren, S.J., Matrisian, L.M., and Parks, W.C.: Regulation of intestinal a-defensin activation by the metalloproteinase matrilysin in innate host defense, Science 286:113-117, 1999. http://www.sciencemag.org/cgi/reprint/286/5437/113.pdf
Tang, Y. -Q., Yuan, J., Ösapay, K., Ösapay, G., Tran, D., Miller, C.J., Ouellette, A.J., and Selsted, M.E.: A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science 286:498-502, 1999. http://www.sciencemag.org/cgi/reprint/286/5439/498.pdf
NIH 2 R01 DK 4632-13 Ouellette (PI) 05/01/00-04/30/05
Peptide effectors of enteric host defense
Human Frontiers Science Program Gizeli (PI) 08-01-04 to 07-31-07
Mechanisms of antimicrobial peptide interactions with the target cell membrane
U.S.-Israel Binational Science Fdn (Jelinek, Ouellette, Co-PIs) 09/01/02-08/31/06
Novel biomimetic approaches to investigate defensin microbicidal mechanisms.
American Society for Biochemisty
and Molecular Biology, American Society for
American Gastroenterological Associatio
Immunology and Pathogenesis
Center for Immunology