Projects
Name
Role of pH receptors in intestinal fibrosis
University
Switzerland (Swimsa) - University of Zurich, Zurich
Domain
Gastroenterology
Departement
Gastroenterology and Hepatology
Head
Prof. Dr. med Dr. phil. Gerhard Rogler
Tutor
Prof. Dr. med. Dr. phil. Gerhard Rogler, Prof. Dr. rer. nat. Martin Hausmann, Silvia Lang
Languages
English
Duration
4 weeks
Availability
Cities/Months Jan Feb Mar Apr May Jun Jul Augt Sep Oct Nov Dec
Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes
Type of Research Project
- Basic science
What is the background of the project?
Maintaining an appropriate tissue pH has become a challenge for any organism since life left the oceans. Any tissue injury/remodelling that occurs within pathological conditions such as inflammation or fibrosis is associated with an acidic pH shift and local proton accumulation. Three G-protein coupled receptor (GPRs) were identified as biological sentinels for proton concentration: GPR4, ovarian cancer receptor 1 (OGR1/GPR68) and T cell death-associated gene 8 (TDAG8/GPR65). Activation of GPR4 and OGR1 leads to inflammatory cell responses, fibrosis and plays a crucial role in tumour biology, including tumorigenesis, tumour growth, and metastasis. In contrast, TDAG8 has anti-inflammatory properties. Given the unique and outstanding biological role of pH-sensing receptors under these pathophysiological conditions, their modulation/blockade is a highly promising therapeutic option in inflammatory diseases, fibrosis and tumour development. The target of the whole project is to develop a basis for pharmacological interventions on the level of pH-sensing to come to a completely new class of medical or biological (via microbiota manipulation) treatment of a broad range of diseases. The project is divided in to five subprojects, which are closely connected and needed to achieve this goal. I and my research group could show that pH-sensing receptors play a crucial role not only in the pathogenesis of inflammatory bowel disease (IBD), but also during intestinal fibrosis development and also in colorectal carcinoma development. We identified their role for mucosal barrier function and have evidence for regulation by microbiota.
What is the aim of the project?
The aim of our research group is to elucidate the interaction of the activity of the pH-sensing receptors on a molecular (and pharmacological) level And to elucidate the role of pH-sensing receptors in (further) fibrotic diseases.
What techniques and methods are used?
Cell culture (passing of cells, addition of agent of interest) Polymerase chain reaction (primer and DNA of interest addition, PCR machine fine tuning and subsequent cycling) Immunohistochemistry (technique where, using a light microscope, specific antibodies combined with fluorescent dyes are used to target specific biomolecules), Tissue preparation, fixation and staining of said tissue with primary and secondary antibodies. Imaging the signal using a microscope.
What is the role of the student?
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will be asked to take care of cell cultures and treat them accordingly to our standards. Students will observe the growth of cell cultures and the cell cultures will be gained, fixed and coloured. The student will perform PCR with matierial collected from the cell culture and primers designed by the lab and immunhistochemistry and analysing the pattern that might arise from the images acquired. They will help to analyze the collected Data.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
yes
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Good knowledge of English, Motivation, Interest in biomedical and basis research
Are there any legal limitations in the student’s involvement
No
Hours
8
Type of students accepted
This project accepts:
- Medical students
- Graduated students (less than 6 months)
- Students in biomedical fields
Articles
- The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation. Tcymbarevich IV; Eloranta JJ; Rossel JB; Obialo N; Spalinger M; Cosin-Roger J; Lang S; Kullak-Ublick GA; Wagner CA; Scharl M; Seuwen K; Ruiz PA; Rogler G; de Vallière C; Misselwitz B; Swiss IBD Cohort Study Group. BMC Gastroenterol. 2019 Jan 7;19(1):2.
- Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease. Tcymbarevich I; Richards SM; Russo G; Kühn-Georgijevic J; Cosin-Roger J; Baebler K; Lang S; Bengs S; Atrott K; Bettoni C; Gruber S; Frey-Wagner I; Scharl M; Misselwitz B; Wagner CA; Seuwen K; Rogler G; Ruiz PA; Spalinger M; de Vallière C. J Crohns Colitis. 2019 Feb 1;13(2):245-258.
- Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis. Hutter S; van Haaften WT; Hünerwadel A; Baebler K; Herfarth N; Raselli T; Mamie C; Misselwitz B; Rogler G; Weder B; Dijkstra G; Meier CF; de Vallière C; Weber A; Imenez Silva PH; Wagner CA; Frey-Wagner I; Ruiz PA; Hausmann M. J Crohns Colitis. 2018 Nov 15;12(11):1348-1358
- The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation. Wang Y; de Vallière C; Imenez Silva PH; Leonardi I; Gruber S; Gerstgrasser A; Melhem H; Weber A; Leucht K; Wolfram L; Hausmann M; Krieg C; Thomasson K; Boyman O; Frey-Wagner I; Rogler G; Wagner CA. J Crohns Colitis. 2018 Feb 28;12(3):355-368.
- Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Cosin-Roger J; Simmen S; Melhem H; Atrott K; Frey-Wagner I; Hausmann M; de Vallière C; Spalinger MR; Spielmann P; Wenger RH; Zeitz J; Vavricka SR; Rogler G; Ruiz PA. Nat Commun. 2017 Jul 24;8(1):98.
- Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein-Coupled Receptor OGR1 (GPR68). de Vallière C; Cosin-Roger J; Simmen S; Atrott K; Melhem H; Zeitz J; Madanchi M; Tcymbarevich I; Fried M; Kullak-Ublick GA; Vavricka SR; Misselwitz B; Seuwen K; Wagner CA; Eloranta JJ; Rogler G; Ruiz PA. Cell Mol Gastroenterol Hepatol. 2016 Jun 25;2(6):796-810
- Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein-Coupled Receptor OGR1 (GPR68). de Vallière C; Cosin-Roger J; Simmen S; Atrott K; Melhem H; Zeitz J; Madanchi M; Tcymbarevich I; Fried M; Kullak-Ublick GA; Vavricka SR; Misselwitz B; Seuwen K; Wagner CA; Eloranta JJ; Rogler G; Ruiz PA. Cell Mol Gastroenterol Hepatol. 2016 Jun 25;2(6):796-810
- G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation. de Vallière C; Wang Y; Eloranta JJ; Vidal S; Clay I; Spalinger MR; Tcymbarevich I; Terhalle A; Ludwig MG; Suply T; Fried M; Kullak-Ublick GA; Frey-Wagner I; Scharl M; Seuwen K; Wagner CA; Rogler G. Inflamm Bowel Dis. 2015 Jun;21(6):1269-81.