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Regulation of intestinal glucocorticoid synthesis by EGF receptor-induced signaling pathways

English title Regulation of intestinal glucocorticoid synthesis by EGF receptor-induced signaling pathways
Applicant Brunner Thomas
Number 121854
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.02.2009 - 31.01.2012
Approved amount 374'400.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Endocrinology

Keywords (6)

mucosal immunology; glucocorticoid synthesis; gastroenterology; immunopathology; epithelial cells; endocrinology

Lay Summary (German)

Lead
Lay summary
Das intestinale Epithel hat nicht nur eine wichtige Rolle in der Resorption von Nahrungsmitteln, aber auch als physische Barriere um unseren Körper vor dem Eindringen von pathogenen Keimen zu schützen. Intestinale Epithelzellen sind nur kurzlebig und werden konstant durch Proliferation und Differenzierung von epithelialen Stammzellen erneuert. Signale über den Epidermal Growth Factor (EGF) Rezeptor spielen eine wichtige Rolle in der Regulation der Homeostase des intestinalen Epithels. Die intestinale Mucosa beherbergt das zahlenmässig grösste Immunsystem unseres Körpers und spielt eine wichtige Rolle in der Abwehr von Mikroroganismen. Unkontrollierte Immunantworten im Darm können jedoch zu schweren Erkrankungen führen, wie Morbus Crohn oder Colitis Ulcerosa. Aus diesem Grunde müssen Immunantworten im Darm streng kontrolliert werden. Kürzlich konnten wir aufzeigen, dass die lokale Synthese von immunsuppressiven Glucocorticoiden im Darmepithel eine wichtige Rolle in diesen Prozessen spielt. Ebenso konnten wir zeigen, dass der nukleäre Rezeptor und Transkriptionsfaktor Liver Receptor Homolog-1 (LRH-1) die Expression von steroiden Enzymen im Darmepithel und somit die Synthese von Glucocorticoiden reguliert.Ziel dieser Studie ist die Charakterisierung der Signaltransduktionswege, welche zur Aktivierung von LRH-1 und der Synthese von Glucocorticoiden in Darmepithelzellen führt. Speziell interessiert sind wir an der Rolle des durch den EGF Rezeptor-aktivierten MAP Kinase Signaltransduktionsweges in der Phosphorylierung und Aktivierung von LRH-1 und der damit verbundenen Induktion der Glucocorticoidsynthese. Daneben möchten wir die Rolle der nukleären Rezeptoren SHP und Prox1 charakterisieren, welche die Aktivierung von LRH-1 inhibieren können. Schlussendlich möchten wir verstehen ob LRH-1 nicht nur ein zentraler Regulator der intestinalen Glucocorticoidsynthese darstellt, sondern auch das Ueberleben der intestinalen Epithelzellen beeinflusst.Die geplanten Studien sollen einen vertieften Einblick geben in die bisher unerforschte Regulation der extra-adrenalen Glucocorticoidsynthese im Darm und deren Rolle in der Aufrechterhaltung der lokalen Immunhomeostase.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Local glucocorticoid production in the mouse lung is induced by immune cell stimulation.
Hostettler N, Bianchi P, Gennari-Moser C, Kassahn D, Schoonjans K, Corazza N, Brunner T (2012), Local glucocorticoid production in the mouse lung is induced by immune cell stimulation., in Allergy, 67(2), 227-34.
The proapoptotic Bcl-2 family member Bim plays a central role during the development of virus-induced hepatitis.
Lauer Christoph, Brunner Thomas, Corazza Nadia (2012), The proapoptotic Bcl-2 family member Bim plays a central role during the development of virus-induced hepatitis., in Journal of immunology (Baltimore, Md. : 1950), 188(2), 916-22.
Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage.
Badmann A, Keough A, Kaufmann T, Bouillet P, Brunner T, Corazza N (2011), Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage., in Cell death & disease, 2, 171-171.
Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel.
Sidler D, Brockmann A, Mueller J, Nachbur U, Corazza N, Renzulli P, Hemphill A, Brunner T (2011), Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel., in Oncogene, xx-xx.
Colon cancer cells produce immunoregulatory glucocorticoids.
Sidler D, Renzulli P, Schnoz C, Berger B, Schneider-Jakob S, Flück C, Inderbitzin D, Corazza N, Candinas D, Brunner T (2011), Colon cancer cells produce immunoregulatory glucocorticoids., in Oncogene, 30(21), 2411-9.
Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner.
Schmich Kathrin, Schlatter Rebekka, Corazza Nadia, Sá Ferreira Karine, Ederer Michael, Brunner Thomas, Borner Christoph, Merfort Irmgard (2011), Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner., in Hepatology (Baltimore, Md.), 53(1), 282-92.
Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid.
Schneider-Jakob S, Corazza N, Badmann A, Sidler D, Stuber-Roos R, Keogh A, Frese S, Tschan M, Brunner T (2010), Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid., in Cell death & disease, 1, 86-86.
Control of death receptor ligand activity by posttranslational modifications.
Weinlich R, Brunner T, Amarante-Mendes G P (2010), Control of death receptor ligand activity by posttranslational modifications., in Cellular and molecular life sciences : CMLS, 67(10), 1631-42.
Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner.
Noti Mario, Corazza Nadia, Tuffin Gérald, Schoonjans Kristina, Brunner Thomas (2010), Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 24(5), 1340-6.
Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer.
Karamitopoulou Eva, Pallante Pierlorenzo, Zlobec Inti, Tornillo Luigi, Carafa Vincenza, Schaffner Thomas, Borner Markus, Diamantis Ioannis, Esposito Francesco, Brunner Thomas, Zimmermann Arthur, Federico Antonella, Terracciano Luigi, Fusco Alfredo (2010), Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer., in European journal of cancer (Oxford, England : 1990), 46(8), 1438-44.
TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis.
Noti Mario, Corazza Nadia, Mueller Christoph, Berger Barbara, Brunner Thomas (2010), TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis., in The Journal of experimental medicine, 207(5), 1057-66.
Differential cell cycle and proliferation marker expression in ductal pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia (PanIN).
Karamitopoulou Eva, Zlobec Inti, Tornillo Luigi, Carafa Vincenza, Schaffner Thomas, Brunner Thomas, Borner Markus, Diamantis Ioannis, Zimmermann Arthur, Terracciano Luigi (2010), Differential cell cycle and proliferation marker expression in ductal pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia (PanIN)., in Pathology, 42(3), 229-34.
Prognostic significance of apoptotic cell death in bladder cancer: a tissue microarray study on 179 urothelial carcinomas from cystectomy specimens.
Karamitopoulou Eva, Rentsch Cyrill A, Markwalder Regula, Vallan Claudio, Thalmann George N, Brunner Thomas (2010), Prognostic significance of apoptotic cell death in bladder cancer: a tissue microarray study on 179 urothelial carcinomas from cystectomy specimens., in Pathology, 42(1), 37-42.
Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death.
Müller Stefan, Rihs Silvia, Schneider Johanna M Dayer, Paredes Bruno E, Seibold Ingeborg, Brunner Thomas, Mueller Christoph (2009), Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death., in European journal of immunology, 39(11), 3171-80.
TRAIL-induced apoptosis: between tumor therapy and immunopathology.
Corazza Nadia, Kassahn Daniela, Jakob Sabine, Badmann Anastasia, Brunner Thomas (2009), TRAIL-induced apoptosis: between tumor therapy and immunopathology., in Annals of the New York Academy of Sciences, 1171, 50-8.
Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean?
Noti Mario, Sidler Daniel, Brunner Thomas (2009), Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean?, in Seminars in immunopathology, 31(2), 237-48.
Living on the edge: immune cells and immunopathology in the intestinal mucosa.
Brunner Thomas (2009), Living on the edge: immune cells and immunopathology in the intestinal mucosa., in Seminars in immunopathology, 31(2), 143-4.
miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer.
Bandi Nora, Zbinden Samuel, Gugger Mathias, Arnold Marlene, Kocher Verena, Hasan Lara, Kappeler Andreas, Brunner Thomas, Vassella Erik (2009), miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer., in Cancer research, 69(13), 5553-9.
Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells.
Kassahn D, Nachbur U, Conus S, Micheau O, Schneider P, Simon H-U, Brunner T (2009), Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells., in Cell death and differentiation, 16(1), 115-24.

Associated projects

Number Title Start Funding scheme
110030 Molecular control of the glucocorticoid synthesis in the intestinal mucosa 01.02.2006 Project funding (Div. I-III)

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