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The role of pH sensing G-protein coupled receptors for intestinal inflammation and fibrosis

English title The role of pH sensing G-protein coupled receptors for intestinal inflammation and fibrosis
Applicant Rogler Gerhard
Number 172870
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.05.2017 - 30.04.2020
Approved amount 600'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Physiology : other topics

Keywords (6)

pH receptors; Crohn’s disease; innate immunity; G-protein coupled receptors; barrier function; mucosal immune system

Lay Summary (German)

Lead
pH Rezeptoren und Darmerkrankungen
Lay summary
Im gesunden Gewebe wird der pH-Wert normalerweise in einem engen Bereich um pH 7,4 hauptsächlich durch Regulierung über die Atmung und renale Säure-Ausscheidung gehalten. Bei entzündlichen Darmerkrankungen (IBD) ist die Darmwandentzündung mit einer extrazellulären Ansäurerung verbunden, die sowohl die Progression als auch die Heilung der Entzündung beeinflusst. Der reduzierte extrazelluläre pH-Wert aktiviert spezifische zelluläre Signalwege, insbesondere über Proteine der G-Protein-gekoppelten Rezeptor (GPCR) -Familie. Die GPR4-Unterfamilie umfasst neben GPR4 auch OGR1 (GPR68) und T-Zelltod-assoziiertes Gen 8 (TDAG8) (GPR65). Es wurde gezeigt, dass diese Rezeptoren den extrazellulären pH-Wert über die Bindung von H + -Ionen erfassen.
Als Reaktion auf die extrazelluläre Säuerung stimulieren Ph-Sensing-GPRs eine Vielzahl von intrazellulären Signalwegen. Viele Daten zeigen, dass die Protonen-Sensing-GPRs bei pH 7,8 bis 7,6 inaktiv oder nur wenig aktiv sind, aber bereits bei einem pH Werte von pH 6,8 maximal aktiv sind. PH-Sensing-GPRs werden hauptsächlich in Makrophagen und anderen Zellen des angeborenen Immunsystems sowie intestinalen Epithelzellen gefunden. Beide Zelltypen spielen bei der Entstehung von IBD eine entscheidende Rolle.
Vor kurzem haben wir gezeigt, dass das Fehlen von GPR4 oder OGR1 in Tiermodellen der Dickdarmentzündung (Colitis) schützend wirkt. Wir haben weitere Hinweise darauf, dass OGR1 während der Entstehung von Narben im Darm eine sehr wichtige Rolle spielt. Darüber hinaus konnten wir nachweisen, dass OGR1 Reaktionen auf Sauerstoffmangel vermittelt.
Das langfristige Ziel des Projekts ist ein besseres Verständnis der grundlegenden Schleimhautentzündungs-Mechanismen und die Entwicklung neuer Behandlungsmöglichkeiten ("pH-Rezeptorblocker", "OGR1-Antagonisten") für chronische Darmentzündungen (IBD) und Darmfibrose.

Direct link to Lay Summary Last update: 13.04.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease
Tcymbarevich Irina, Richards Shola M, Russo Giancarlo, Kühn-Georgijevic Jelena, Cosin-Roger Jesus, Baebler Katharina, Lang Silvia, Bengs Susan, Atrott Kirstin, Bettoni Carla, Gruber Sven, Frey-Wagner Isabelle, Scharl Michael, Misselwitz Benjamin, Wagner Carsten A, Seuwen Klaus, Rogler Gerhard, Ruiz Pedro A, Spalinger Marianne, de Vallière Cheryl (2019), Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease, in Journal of Crohn's and Colitis, 13(2), 245-258.
The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.
Tcymbarevich Irina (2019), The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation., in BMC Gastroenterol, 19, 2.
Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis
Hutter Senta, van Haaften Wouter T, Hünerwadel Anouk, Baebler Katharina, Herfarth Neel, Raselli Tina, Mamie Céline, Misselwitz Benjamin, Rogler Gerhard, Weder Bruce, Dijkstra Gerard, Meier Chantal Florence, de Vallière Cheryl, Weber Achim, Imenez Silva Pedro H, Wagner Carsten A, Frey-Wagner Isabelle, Ruiz Pedro A, Hausmann Martin (2018), Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis, in Journal of Crohn's and Colitis, 15, 1348-1358.
The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation
Wang Yu, de Vallière Cheryl, Imenez Silva Pedro H, Leonardi Irina, Gruber Sven, Gerstgrasser Alexandra, Melhem Hassan, Weber Achim, Leucht Katharina, Wolfram Lutz, Hausmann Martin, Krieg Carsten, Thomasson Koray, Boyman Onur, Frey-Wagner Isabelle, Rogler Gerhard, Wagner Carsten A (2018), The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation, in Journal of Crohn's and Colitis, 12(3), 355-368.
Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
Cosin-Roger Jesus, Simmen Simona, Melhem Hassan, Atrott Kirstin, Frey-Wagner Isabelle, Hausmann Martin, de Vallière Cheryl, Spalinger Marianne R., Spielmann Patrick, Wenger Roland H., Zeitz Jonas, Vavricka Stephan R., Rogler Gerhard, Ruiz Pedro A. (2017), Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation, in Nature Communications, 8(1), 98-98.

Collaboration

Group / person Country
Types of collaboration
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Gr Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Institute of Physiology, University of Zürich, Zürich, Switzerland., Prof. Carsten Wagner Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Declan McCole, Riverside, Californien, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Klaus Seuwen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Industry/business/other use-inspired collaboration

Associated projects

Number Title Start Funding scheme
134274 Schweizer IBD Kohorten Studie 01.04.2011 Cohort Studies Large
166844 Multi-center, multi-national, double-blind, placebo controlled study to evaluate the efficacy and safety of an anthocyanin-rich extract (ACRE) in moderately active ulcerative colitis 01.06.2016 Investigator Initiated Clinical Trials (IICT)
148422 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2014 Cohort Studies Large
170109 Dietary nanoparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study 01.10.2016 Project funding (special)

Abstract

In uninflamed tissue, pH is normally maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. In both forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), the gut-wall inflammation is associated with extracellular tissue acidification, which affects both, progression and resolution of inflammation. Low extracellular pH activates specific sensory pathways, in particular proteins of the G protein-coupled receptor (GPCR) family. The GPR4 subfamily consists of three GPCRs that share significant sequence homology. In addition to GPR4, this subfamily includes OGR1 (GPR68) and T cell death-associated gene 8 (TDAG8) (GPR65). They have been identified to sense extracellular pH after binding H+ ions. A common feature of this family of pH-sensing receptors is their role in the regulation of inflammatory and immune responses and tumorigenesis. In response to extracellular acidification, ph sensing GPRs stimulate a variety of intracellular signalling pathways, including Gs/adenylyl cyclase/cAMP and G13/Rho. Accumulating evidence indicates that the proton-sensing GPRs are inactive or only slightly active at pH 7.8 to 7.6 but become maximally active around pH 6.8. pH sensing GPRs are mainly found in macrophages and other cells of the innate immune system as well as intestinal epithelial cells. Both cell types play a crucial role during the pathogenesis of IBD. Recently we showed that the deletion of GPR4 or OGR1 protects from DSS induced colitis or ameliorates colitis in IL10/pH receptor double knockout mice. Additionally, OGR1 inhibited epithelial cell migration in an acidic environment. We have further evidence that OGR1 Plays a very important tole during the pathogenesis of intestinal fibrosis. In addition we could demonstrate that OGR1 mediates Responses to hypoxia and induces ER stress reactions.This important physiological role of pH sensing GPRs will be further investigated based of the following hypotheses:1) G-protein coupled pH receptors play an important role during responses to ER stress and hypoxia subsequently regulating inflammation.2) G-protein coupled pH receptors (e.g. OGR-1) play an essential role during intestinal fibrosis.3) OGR1/GPR4 on one hand and TDAG8 on the other have antagonistic roles in fine-tuning immune responses.The long term goal will be a better understanding of basic mucosal inflammatory mechanisms and the development of new treatment options (“pH receptor blockers”; “OGR1 antagonists”) for chronic mucosal inflammatory diseases and intestinal fibrosis.
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