Intestinale mukosale Wundheilung im Rahmen entzündlicher Veränderungen im Gastrointestinaltrakt
Final Report Abstract
The above projects represent a reasonable integration of my past research experience in cell biology and my present interest in studying pathophysiologic mechanisms of gastrointestinal tract diseases such as IBD. We still know little about mechanisms influencing intestinal epithelial inflammation. My studies not only provided important information related to the pathophysiology of intestinal inflammation and apoptosis but also provided potential insights into therapeutic approaches that can be used for the treatment in IBD. We explored a novel mechanism by which a pro-inflammatory cytokine, IFN-y mediates epithelial apoptosis during intestinal inflammation through antagonizing the Wnt signaling pathway. Moreover our studies highlight a novel mechanism by which Dsg2 regulates IEC apoptosis driven by cysteine proteases during physiological differentiation and inflammation. Finally we could identify for the first time a tight junction protein (JAM-A) responsible for intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation. Since we found several new functions related to one of the main players (IFN-y) in inflammation, the future work will be directed in exploring the role of the cytokine and its receptor in the onset of colitis. We already got promising preliminary data in animal experiments suggesting the receptor of IFN-y to be actively involved in the regulation of inflammation. This will be a potential topic of a further grant to be submitted. Moreover we got preliminary data indicating DKK-1 to be a potential serum marker in inflammation. Since we now have the infrastructure in Münster as well the contacts and the support at Emory, we plan to exchange further results on a new established web site for an easier and faster communication and cooperation. Moreover Emory provides access to murine knock out animals for studying the role of IFN-y in inflammation. At present members of the inflammatory bowel disease group in Münster are the departments of Medicine (Director: Prof. Dr. Dr. h.c. W. Domschke). Paediatrics (Director: Prof. Dr. E. Harms), and the Department of Vascular Cell Biology of the Max-Planck Institute for Molecular Biomedicine (Director: Prof. Dr. D. Vestweber).
Publications
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Regulation of the intestinal epithelial barrier by the apical junctional complex. Curr Opin Gastroenterol. 2006 Mar;22(2):85-9
Laukoetter MG, BruewerM, Nusrat A
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Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal Epithelium. Mol Biol Cell. 2007 Nov;18(11):4565-78. Epub 2007 Sep 5s
Porfirio Nava, Mike G. Laukoetter, Ann M. Hopkins, Oskar Laur, Kirsten Gerner-Smidt, Kathleen J. Green, Charles A. Parkos, and Asma Nusrat
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Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-depondent activation of Rac1 and Cdc42. J Immunol. 2007 Dec 15;179(12):8112-21
Brian A. Babbin, Algirdas J. Jesaitis, Andrei I. Ivanov, Daina Kelly, Mike G. Laukoetter, Porfirio Nava, Charles A. Parkos and Asma Nusrat
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JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med. 2007 Dec 24;204(13):3067-76
Mike G. Laukoetter, Porfirio Nava, Winston Y. Lee, Eric A. Severson, Christopher T. Capaldo, Brian A. Babbin, Ifor R. Williams, Michael Koval, Eric Peatman, Jacquelyn A. Campbell, Terence S. Dermody, Asma Nusrat, and Charles A. Parkos
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Organized migration of epithelial cells requires control of adhesion and protrusion through Rho kinase effectors. Am J Physiol Gastrointest Liver Physiol. 2007 Mar;292(3):G806-17
Ann M. Hopkins, A'Drian A. Pineda, L. Matthew Winfree, G. Thomas Brown, Mike G. Laukoetter, and Asma Nusrat
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Role of the intestinal barrier in inflammatory bowel disease. World J Gastroenterol. 2008 Jan 21;14(3):401-7
Mike G Laukoetter, Porfirio Nava, Asma Nusrat
