Project

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The role of SLC transporters in autophagy and inflammatory bowel disease

English title The role of SLC transporters in autophagy and inflammatory bowel disease
Applicant Vavricka Stephan
Number 135694
Funding scheme Project funding (special)
Research institution Medizinische Klinik Stadtspital Triemli
Institution of higher education University of Zurich - ZH
Main discipline Molecular Biology
Start/End 01.04.2011 - 31.03.2014
Approved amount 288'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Cellular Biology, Cytology

Keywords (12)

intestinal transporters; inflammation; tumor necrosis factor alpha; pro-inflammatory cytokines; autophagy; hypoxia; apoptosis; inflammatory bowel disease; bacteria-derived peptides; solute carrier transporters; large nested project; Swiss Inflamatory Bowel Disease Cohort Study

Lay Summary (English)

Lead
Lay summary

When aberrant, it contributes to human inflammatory disorders. Mutations in autophagy genes (ATG16L1 and IRGM) have been described as susceptibility factors of CD. Properly functioning autophagy prevents autoimmunity, assists in clearing pathogens, and plays a protective role during cell stress and injury. Normally the intruded bacteria-derived products are cleared from the intestinal wall by a process called autophagy. Autophagocytosis degrades aggregated proteins, removes damaged organelles, and eliminates intracellular microbes and bacteria-derived products. Inflammatory bowel disease (IBD) is a disorder characterized by chronic inflammation of the intestinal mucosa. The pathophysiology of IBD depends on both genetic susceptibility and environmental factors. Absorption and transport of solutes in the intestine are significantly perturbed during the course of IBD. Recently, we analyzed alterations in the intestinal expression levels of 15 solute carrier (SLC) transporters in healthy individuals and IBD patients. It has been demonstrated that pro-inflammatory cytokines, such as TNF and IFN-? induce the expression of human peptide transporter (hPEPT1), which transports muramyl dipeptide (MDP) a bacterial wall component of Gram-positive and Gram-negative bacteria. When present in the cytosol MDP activates Nod2, which can start the cascade of pro-inflammatory signaling. Background:

 

We postulate that the alteration in expression levels of SLC transporters in IBD patients is due to the effects of circulating pro-inflammatory cytokines and hypoxic conditions. Working Hypothesis:Our studies indicate that this may affect the absorption and transport of nutrients and biologically active compounds, including drugs, amino acids, and bacteria-derived products such as bacterial peptidoglycans (PGln), which in turn modulate autophagy and innate immune response.

 

The proposed study aims at the understanding of molecular mechanisms involved in the pathogenesis of IBD. Based on the current knowledge of the subject and both on our published and preliminary results we expect to gather essential information about the role of intestinal transporters in the pathology of IBD. :Proposed Project Expected Value of the

Keywords: solute carrier, intestinal transporters, inflammation, pro-inflammatory cytokines, autophagy, hypoxia, inflammatory bowel disease, bacteria-derived peptides, hypoxia

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients.
Vavricka Stephan R, Rogler Gerhard, Maetzler Sandra, Misselwitz Benjamin, Safroneeva Ekaterina, Frei Pascal, Manser Christine N, Biedermann Luc, Fried Michael, Higgins Peter, Wojtal Kacper A, Schoepfer Alain M (2014), High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients., in Journal of Crohn's & colitis, 8(3), 191-9.
Induction or Exacerbation of Psoriasis in Patients with Crohn's Disease under Treatment with Anti-TNF Antibodies.
Barthel Christiane, Biedermann Luc, Frei Pascal, Vavricka Stephan R, Kündig Thomas, Fried Michael, Rogler Gerhard, Scharl Michael (2014), Induction or Exacerbation of Psoriasis in Patients with Crohn's Disease under Treatment with Anti-TNF Antibodies., in Digestion, 89(3), 209-215.
Prevalence of anemia in inflammatory bowel diseases in european countries: a systematic review and individual patient data meta-analysis.
Filmann Natalie, Rey Julia, Schneeweiss Sven, Ardizzone Sandro, Bager Palle, Bergamaschi Gaetano, Koutroubakis Ioannis, Lindgren Stefan, Morena Felipe de la, Moum Bjørn, Vavricka Stephan R, Schröder Oliver, Herrmann Eva, Blumenstein Irina (2014), Prevalence of anemia in inflammatory bowel diseases in european countries: a systematic review and individual patient data meta-analysis., in Inflammatory bowel diseases, 20(5), 936-45.
Steroid Use in Crohn's Disease
Vavricka Stephan R., Schoepfer Alain M., Scharl Michael, Rogler Gerhard (2014), Steroid Use in Crohn's Disease, in DRUGS, 74(3), 313-324.
Steroid use in Crohn's disease.
Vavricka Stephan R, Schoepfer Alain M, Scharl Michael, Rogler Gerhard (2014), Steroid use in Crohn's disease., in Drugs, 74(3), 313-24.
A Role for Tumor Necrosis Factor and Bacterial Antigens in the Pathogenesis of Crohn's Disease-Associated Fistulae
Frei Sandra Michaela, Pesch Theresa, Lang Silvia, Weber Achim, Jehle Ekkehard, Vavricka Stephan R., Fried Michael, Rogler Gerhard, Scharl Michael (2013), A Role for Tumor Necrosis Factor and Bacterial Antigens in the Pathogenesis of Crohn's Disease-Associated Fistulae, in INFLAMMATORY BOWEL DISEASES, 19(13), 2878-2887.
Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis - an open pilot study.
Biedermann Luc, Mwinyi Jessica, Scharl Michael, Frei Pascal, Zeitz Jonas, Kullak-Ublick Gerd A, Vavricka Stephan R, Fried Michael, Weber Achim, Humpf Hans-Ulrich, Peschke Simone, Jetter Alexander, Krammer Gerhard, Rogler Gerhard (2013), Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis - an open pilot study., in Journal of Crohn's & colitis, 7(4), 271-9.
Concept for a rapid point-of-care calprotectin diagnostic test for diagnosis and disease activity monitoring in patients with inflammatory bowel disease: expert clinical opinion.
Rogler Gerhard, Aldeguer Xavier, Kruis Wolfgang, Lasson Anders, Mittmann Ulrich, Nally Ken, Peyrin-Biroulet Laurent, Schoepfer Alain, Vatn Morten, Vavricka Stephan, Logan Robert (2013), Concept for a rapid point-of-care calprotectin diagnostic test for diagnosis and disease activity monitoring in patients with inflammatory bowel disease: expert clinical opinion., in Journal of Crohn's & colitis, 7(8), 670-7.
Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.
Schoepfer Alain M, Beglinger Christoph, Straumann Alex, Safroneeva Ekaterina, Romero Yvonne, Armstrong David, Schmidt Carsten, Trummler Michael, Pittet Valérie, Vavricka Stephan R (2013), Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes., in Inflammatory bowel diseases, 19(2), 332-41.
Mucosal healing and deep remission: what does it mean?
Rogler Gerhard, Vavricka Stephan, Schoepfer Alain, Lakatos Peter L (2013), Mucosal healing and deep remission: what does it mean?, in World journal of gastroenterology : WJG, 19(43), 7552-60.
Mucosal healing and deep remission: What does it mean?
Rogler Gerhard, Vavricka Stephan, Schoepfer Alain, Lakatos Peter L. (2013), Mucosal healing and deep remission: What does it mean?, in WORLD JOURNAL OF GASTROENTEROLOGY, 19(43), 7552-7560.
Mucosal healing and deep remission: what does it mean?
Rogler Gerhard, Vavricka Stephan, Schoepfer Alain, Lakatos Peter L (2013), Mucosal healing and deep remission: what does it mean?, in World journal of gastroenterology : WJG, 19(43), 7552-60.
Periodontitis and Gingivitis in Inflammatory Bowel Disease: A Case-Control Study
Vavricka Stephan R., Manser Christine N., Hediger Sebastian, Voegelin Marius, Scharl Michael, Biedermann Luc, Rogler Sebastian, Seibold Frank, Sanderink Rene, Attin Thomas, Schoepfer Alain, Fried Michael, Rogler Gerhard, Frei Pascal (2013), Periodontitis and Gingivitis in Inflammatory Bowel Disease: A Case-Control Study, in INFLAMMATORY BOWEL DISEASES, 19(13), 2768-2777.
Review: New anti-cytokines for IBD: what is in the pipeline?
Scharl Michael, Vavricka Stephan R, Rogler Gerhard (2013), Review: New anti-cytokines for IBD: what is in the pipeline?, in Current drug targets, 11(1), 1-1.
Review: new anti-cytokines for IBD: what is in the pipeline?
Scharl Michael, Vavricka Stephan R, Rogler Gerhard (2013), Review: new anti-cytokines for IBD: what is in the pipeline?, in Current drug targets, 14(12), 1405-20.
Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans.
Biedermann Luc, Zeitz Jonas, Mwinyi Jessica, Sutter-Minder Eveline, Rehman Ateequr, Ott Stephan J, Steurer-Stey Claudia, Frei Anja, Frei Pascal, Scharl Michael, Loessner Martin J, Vavricka Stephan R, Fried Michael, Schreiber Stefan, Schuppler Markus, Rogler Gerhard (2013), Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans., in PloS one, 8(3), 59260-59260.
The effects of vitamin A on cells of innate immunity in vitro.
Wojtal Kacper A, Wolfram Lutz, Frey-Wagner Isabelle, Lang Silvia, Scharl Michael, Vavricka Stephan R, Rogler Gerhard (2013), The effects of vitamin A on cells of innate immunity in vitro., in Toxicology in vitro : an international journal published in association with BIBRA, 27(5), 1525-1532.
Fc gamma receptor CD64 modulates the inhibitory activity of infliximab.
Wojtal Kacper A, Rogler Gerhard, Scharl Michael, Biedermann Luc, Frei Pascal, Fried Michael, Weber Achim, Eloranta Jyrki J, Kullak-Ublick Gerd A, Vavricka Stephan R (2012), Fc gamma receptor CD64 modulates the inhibitory activity of infliximab., in PloS one, 7(8), 43361-43361.
Intestinal absorption and vitamin levels: is a new focus needed?
Vavricka Stephan R, Rogler Gerhard (2012), Intestinal absorption and vitamin levels: is a new focus needed?, in Digestive diseases (Basel, Switzerland), 30 Suppl 3, 73-80.
Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers.
Schoepfer Alain M, Vavricka Stephan, Zahnd-Straumann Nadine, Straumann Alex, Beglinger Christoph (2012), Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers., in Journal of Crohn's & colitis, 6(4), 412-8.
Pregnancy and breastfeeding in inflammatory bowel disease.
Biedermann Luc, Rogler Gerhard, Vavricka Stephan R, Seibold Frank, Seirafi Mariam (2012), Pregnancy and breastfeeding in inflammatory bowel disease., in Digestion, 86 Suppl 1, 45-54.
Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells.
Scharl Michael, Wojtal Kacper A, Becker Helen M, Fischbeck Anne, Frei Pascal, Arikkat Joba, Pesch Theresa, Kellermeier Silvia, Boone David L, Weber Achim, Loessner Martin J, Vavricka Stephan R, Fried Michael, McCole Declan F, Rogler Gerhard (2012), Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells., in Inflammatory bowel diseases, 18(7), 1287-302.
Treatment of extraintestinal manifestations in inflammatory bowel disease.
Lakatos Peter L, Lakatos Laszlo, Kiss Lajos S, Peyrin-Biroulet Laurent, Schoepfer Alain, Vavricka Stephan (2012), Treatment of extraintestinal manifestations in inflammatory bowel disease., in Digestion, 86 Suppl 1, 28-35.

Associated projects

Number Title Start Funding scheme
114009 Role of Bacteria Derived Peptides in Intestinal Epithelial Cells In Health and In Patients With Inflammatory Bowel Disease 01.03.2007 Project funding (Div. I-III)
114009 Role of Bacteria Derived Peptides in Intestinal Epithelial Cells In Health and In Patients With Inflammatory Bowel Disease 01.03.2007 Project funding (Div. I-III)

Abstract

Inflammatory bowel disease (IBD) is a disorder characterized by chronic inflammation of the intestinal mucosa. The pathophysiology of IBD depends on both genetic susceptibility and environmental factors. Absorption and transport of solutes in the intestine are significantly perturbed during the course of IBD. Recently, we analyzed alterations in the intestinal expression levels of 15 solute carrier (SLC) transporters in healthy individuals and IBD patients. It has been demonstrated that pro-inflammatory cytokines, such as TNF and IFN-? induce the expression of human peptide transporter (hPEPT1),11 which transports muramyl dipeptide (MDP) a bacterial wall component of Gram-positive and Gram-negative bacteria. When present in the cytosol MDP activates Nod2, which can start the cascade of pro-inflammatory signaling. Normally the intruded bacteria-derived products are cleared from the intestinal wall by a process called autophagy. Autophagocytosis degrades aggregated proteins, removes damaged organelles, and eliminates intracellular microbes and bacteria-derived products. Properly functioning autophagy prevents autoimmunity, assists in clearing pathogens, and plays a protective role during cell stress and injury. When aberrant, it contributes to human inflammatory disorders. Mutations in autophagy genes (ATG16L1 and IRGM) have been described as susceptibility factors of CD.Working Hypothesis: We postulate that the alteration in expression levels of SLC transporters in IBD patients is due to the effects of circulating pro-inflammatory cytokines and hypoxic conditions. Our studies indicate that this may affect the absorption and transport of nutrients and biologically active compounds, including drugs, amino acids, and bacteria-derived products such as bacterial peptidoglycans (PGln), which in turn modulate autophagy and innate immune response.Specific Aims: (A)Regulation of expression of intestinal SLCs by inflammation (A1) and hypoxia (A2). To investigate the molecular mechanisms controlling the expression of intestinal SLC transporters implicated in IBD we will perform cell line-based studies using human intestinal cell lines treated with a subset of pro-inflammatory cytokines and in animal model of colitis. To study the role of the hypoxic component on the expression of intestinal SLCs we will monitor their expression in individuals which have been exposed to hypoxia. Additionally in order to confirm the findings, cell lines based experiments will be performed.(B) The role of SLC-mediated uptake of bacterial peptides in the induction of autophagy. To study the influence of bacteria-derived peptides on the formation of the autophagosome, we will perform uptake studies using human intestinal cell lines to measure phagocytotic and inflammatory responses. In addition, we will study the uptake of bacterial peptides in phagocytosis-susceptible cell lines from IBD patients carrying implicated mutations in autophagy genes. In addition, we will screen for molecular targets implicated in autophagy (ATG16L1, IGRM, PTPN2/22) and autophagy-relevant SLCs (PEPT-1, ATB(0), PHT-1) using human biopsies from the SwissIBD cohort study (SIBDCS).Expected Value of the Proposed Project: The proposed study aims at the understanding of molecular mechanisms involved in the pathogenesis of IBD. Based on the current knowledge of the subject and both on our published and preliminary results we expect to gather essential information about the role of intestinal transporters in the pathology of IBD.
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