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mRNA splicing and epithelial integrity

English title mRNA splicing and epithelial integrity
Applicant Krebs Philippe
Number 163086
Funding scheme Project funding (special)
Research institution Institut für Pathologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2016 - 31.03.2020
Approved amount 525'000.00
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All Disciplines (5)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology
Experimental Cancer Research
Molecular Biology
Pathophysiology

Keywords (9)

inflammation; inflammatory bowel disease; microbes; mRNA splicing; cancer; immunopathology; mouse models; epithelium; genetic mutations

Lay Summary (French)

Lead
Ce projet consiste à étudier le rôle de l'épissage alternatif des ARNm pour la fonction et l’intégrité de l'épithélium intestinal, ainsi que les conséquences d’une dérégulation de ce mécanisme pour le développement des maladies inflammatoires chroniques de l'intestin ou du cancer colorectal.
Lay summary

L'épithélium intestinal est constitué d’une seule couche de cellules formant une barrière physique entre le corps et l'environnement. L'épithélium de l’intestin interagit avec la flore intestinale et le système immunitaire des muqueuses pour former un micro-environnement complexe dont l’intégrité nécessite une régulation rigoureuse. Des perturbations de l’interaction flore intestinale-système immunitaire conduisent à des troubles intestinaux associés à un dysfonctionnement de l'épithélium, tels que les maladies inflammatoires chroniques de l'intestin (MICI) ou le cancer colorectal (CCR). Plusieurs facteurs environnementaux ou génétiques ont été directement associés à ces maladies. Néanmoins, le rôle des modifications post-transcriptionnelles dans la régulation du développement des MICI ou du CC est peu connu. En particulier, la contribution de l'épissage alternatif des ARN messagers (ARNm) à l’évolution de ces maladies n’a pas encore fait l’objet de recherches approfondies.

Notre hypothèse de travail est qu’une dérégulation du contrôle de l'épissage alternatif des ARNm favorise le développement des MICI ou du CCR. Pour évaluer cette hypothèse, nous emploierons des modèles animaux ainsi que des échantillons de patients atteints de MICI ou du CCR.

Avec ces recherches, nous espérons étendre nos connaissances actuelles sur le rôle de l'épissage alternatif des ARNm dans l’intégrité de l'épithélium intestinal ainsi dans l'initiation ou la progression des MICI ou du CCR. De plus, notre étude a le potentiel de révéler des isoformes de gènes spécifiques à ces maladies qui pourraient servir de biomarqueurs ou de cibles thérapeutiques.

Direct link to Lay Summary Last update: 08.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer
Pastille Eva, Wasmer Marie-Hélène, Adamczyk Alexandra, Vu Vivian P., Mager Lukas F., Phuong Nhi Ngo Thi, Palmieri Vittoria, Simillion Cedric, Hansen Wiebke, Kasper Stefan, Schuler Martin, Muggli Beat, McCoy Kathy D., Buer Jan, Zlobec Inti, Westendorf Astrid M., Krebs Philippe (2019), The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer, in Mucosal Immunology, 1-14.
Keep calm: the intestinal barrier at the interface of peace and war
Thoo Lester, Noti Mario, Krebs Philippe (2019), Keep calm: the intestinal barrier at the interface of peace and war, in Cell Death & Disease, 1/849-13.
Non‐apoptotic TRAIL function modulates NK cell activity during viral infection
Alves Ludmila Cardoso, Berger Michael D, Koutsandreas Thodoris, Kirschke Nick, Lauer Christoph, Spörri Roman, Chatziioannou Aristotelis, Corazza Nadia, Krebs Philippe (2019), Non‐apoptotic TRAIL function modulates NK cell activity during viral infection, in EMBO reports, e48789.
The ESRP1-GPR137 axis contributes to intestinal pathogenesis
Lukas Franz Mager (2017), The ESRP1-GPR137 axis contributes to intestinal pathogenesis, in eLife, 6(e28366), 28366.
The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment
Wasmer Marie-Hélène, Krebs Philippe (2017), The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment, in Frontiers in Immunology, 7, 1-13.
Cytokine-Induced Modulation of Colorectal Cancer
Mager Lukas F., Wasmer Marie-Hélène, Rau Tilman T., Krebs Philippe (2016), Cytokine-Induced Modulation of Colorectal Cancer, in Frontiers in Oncology, 6, 1-19.

Datasets

Assessment of transcript isoforms in Esrp1Triaka versus wild-type primary colonic epithelial cells

Author Keller, Irene
Publication date 29.09.2017
Persistent Identifier (PID) European Nucleotide Archive
Repository European Nucleotide Archive
Abstract
Assessment of transcript isoforms in Esrp1Triaka versus wild-type primary colonic epithelial cells

Non‐apoptotic TRAIL function modulates NK cell activity during viral infection

Author Cardoso Alves, Ludmila; Berger, Michael D; Koutsandreas, Thodoris; Kirschke, Nick; Lauer, Christoph; Spörri, Roman; Chatziioannou, Aristotelis; Corazza, Nadia; Krebs, Philippe
Publication date 04.12.2019
Persistent Identifier (PID) 10.15252/embr.201948789
Repository ArrayExpress
Abstract
Investigation of the change of the Trail-dependent NK cell transcriptome during short-term (24h) infection with lymphocytic choriomeningitis virus (LCMV). RNA sequencing-based transcriptomics analysis was performed in spleen-isolated (NK1.1+CD3-) NK cells from 3 naïve Trail+/+ mice, 3 naive Trail-/- mice, 4 LCMV-infected Trail+/+ mice, and 4 LCMV-infected Trail-/- mice.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Jack Rohrer / ZHAW Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Dr. Rémy Bruggmann / Interfaculty Bioinformatics Unit, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Pascal Juillerat Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Andrew Macpherson and Prof. Kathy McCoy, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Kathy McCoy / University of Calgary Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Christoph Mueller, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Alessandro Lugli and Prof. Inti Zlobec, Institute of Pathology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, Texas, USA United States of America (North America)
- Publication
Christoph Esslinger / Memo Therapeutics AG Switzerland (Europe)
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar Hematology Department, Erasmus Medical Center Rotterdam Individual talk Cytokine‐dependent immunoregulation in cancer and pathology 25.10.2019 Rotterdam, Netherlands Krebs Philippe;
SSAI Annual Congress 2019 Talk given at a conference The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer 05.09.2019 Lugano, Switzerland Krebs Philippe;
Life Science Zürich Microbiology and Immunology Retreat Poster Alternative Splicing Modulates Intestinal Homeostasis & Pathology 31.08.2019 Grindelwald, Switzerland Thoo Lester;
Villa Vigoni Cell Death Meeting 2019 Talk given at a conference Non-apoptotic TRAIL function modulates NK cell activity during viral infection 26.06.2019 Menaggio, Italy Krebs Philippe;
Cutting Edge Topics: Seminars in Immunology & Infection Biology Individual talk T cell regulation during infection and in the tumor environment 26.03.2019 Zurich, Switzerland Krebs Philippe;
GCB Symposium, University of Bern Poster Alternative Splicing Modulates Intestinal Homeostasis & Pathology 31.01.2019 Bern, Switzerland Thoo Lester;
"2nd Young Scientists Meeting in Bern 2019" Talk given at a conference Alternative splicing modulates intestinal homesostasis and pathology 09.01.2019 Bern, Switzerland Krebs Philippe; Thoo Lester;
ZHAW, Wädenswil, seminar Individual talk The ESRP1-GPR137 axis contributes to intestinal pathogenesis 09.05.2018 Wädenswil, Switzerland Krebs Philippe;
Seminar at IRIBHM, Université Libre de Bruxelles (ULB), Brussels, Belgium, seminar Individual talk Transcriptional and post-transcriptional regulation of immunopathology 15.03.2018 Brussels, Belgium Krebs Philippe;
Seminar at Hebrew University of Jerusalem, Jerusalem, Israel Individual talk Transcriptional and post-transcriptional regulation of immunopathology 15.02.2018 Jerusalem, Israel Krebs Philippe;
Wolfsberg Meeting Talk given at a conference Alternative Splicing Modulates Intestinal Homeostasis 08.02.2018 Thun, Switzerland Thoo Lester;
30th Meeting of the Swiss Immunology PhD Students Talk given at a conference Alternative Splicing Modulates Intestinal Homeostasis 07.02.2018 Seepark, Thun, Switzerland Thoo Lester;
12th Graduate School for Cellular and Biomedical Sciences Symposium; University of Bern Poster mRNA Splicing and Epithelial Integrity 01.02.2018 Bern, Switzerland Thoo Lester;
GCB Symposium, University of Bern Poster mRNA Splicing and Epithelial Integrity 01.02.2018 Bern, Switzerland Thoo Lester;
PATIM Seminar Series, Medical Faculty Geneva Individual talk Transcriptional and post-transcriptional regulation of immunopathology 20.10.2017 Geneva, Switzerland Krebs Philippe;
Swiss Society for Allergology and Immunology Annual Meeting 2017 Poster mRNA Splicing and Epithelial Integrity 02.06.2017 St Gallen, Switzerland Thoo Lester;
• Joint Annual Congress of the Swiss Society of Pediatrics and Swiss Society for Allergology and Immunology Poster mRNA Splicing and Epithelial Integrity 01.06.2017 St. Gallen, Switzerland Thoo Lester;
Seminar series of Global Health Institute EPFL Individual talk Alternative mRNA splicing and intestinal pathogenesis 25.04.2017 Lausanne, EPFL, Switzerland Krebs Philippe;
Seminar at University Hospital Regensburg / Gastroenterology Department Individual talk Role of mRNA splicing for intestinal integrity and pathology 01.03.2017 Regensburg , Germany Krebs Philippe;
29th Meeting of the Swiss Immunology PhD Students Poster mRNA Splicing and Epithelial Integrity 06.02.2017 Ermatingen, Switzerland Thoo Lester;
Wolfsberg Meeting Poster mRNA Splicing and Epithelial Integrity 07.01.2017 Wolfsberg , Switzerland Thoo Lester;
Meeting on “Viral Immunity” Talk given at a conference Regulation of T-cell response via modulation of NK cell function 20.10.2016 Milan,, Italy Cardoso Alves Ludmila;
16th Meeting of the Society for Natural Immunity Poster Regulation of T-cell mediated hepatitis via modulation of NK cell function 02.10.2016 Taormina, Italy Cardoso Alves Ludmila;
Swiss Apoptosis Meeting Talk given at a conference A novel, non-apoptotic function for Trail in controlling NK cell activation 08.09.2016 Bern, Switzerland Cardoso Alves Ludmila;
Seminar (Actelion Pharma Schweiz AG, Allschwil/Basel) Individual talk Aberrant alternative mRNA splicing contributes to intestinal pathology in humans and mice 19.08.2016 Allschwil/Basel, Switzerland Krebs Philippe;
Seminar (University Hospital Zürich, Department of gastroenterology and hepatology Individual talk Aberrant alternative mRNA splicing contributes to intestinal pathology in humans and mice 16.06.2016 Zurich, Switzerland Thoo Lester; Krebs Philippe;


Self-organised

Title Date Place
Institute of Pathology Research Retreat 04.05.2018 Kandersteg, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
BSL2 Internal Education for animal caretakers Talk 03.09.2019 Bern, Switzerland Krebs Philippe;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media A new pathway to "reprogram" killer cells UniBE media release International 2019
Media relations: print media, online media Biomarkers Biocentury International 2017
Media relations: print media, online media Der Verdrängungskampf der Krebszellen Neue Zürcher Zeitung German-speaking Switzerland 2017

Awards

Title Year
Best Poster at Life Science Zürich Microbiology and Immunology Retreat, Grindelwald 2019
Swiss National Science Foundation Early Postdoc.Mobility for Lukas Mager (group of Prof. Kathy McCoy; group, University of Calgary, Canada). 2017-2018 2017
Dr. Lutz Zwillenberg-Preis to Lukas Mager for his thesis «Molecular Dissection of Inflammation-induced Immunopathologies» 2016

Associated projects

Number Title Start Funding scheme
138188 Molecular dissection of microbe-induced immunopathlogy 01.09.2012 Project funding (Div. I-III)
145006 Apparatus for Colonoscopy and Endoscopic Manipulations in Mice 01.09.2013 R'EQUIP
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP
121410 A forward genetic approach to uncover novel molecules required for NK cell function and CD8+ T cell priming 01.10.2008 Fellowships for advanced researchers

Abstract

The single-layered intestinal epithelium provides a physical barrier between the body and the environment, which is under the constant challenge from commensals and pathogens. The intestinal epithelium interacts with this microbiota and a specialized mucosal immune system to form a sophisticated network that needs to be tightly regulated. Dysbalance of this complex co-evolved system leads to intestinal disorders such as inflammatory bowel disease (IBD) or colorectal cancer (CRC) that are associated with dysfunction of the epithelium. There is compelling evidence that alterations in the epithelial barrier integrity can lead to uncontrolled inflammation that eventually promotes neoplastic transformation of intestinal epithelial cells (IECs). Besides certain environmental risk factors, several polymorphisms or acquired genetic alterations in key cellular pathways have been reported that underlie IBD or CRC. Yet, the role for posttranscriptional modifications in regulating IBD or CRC development is still elusive. In particular, the contribution of mRNA alternative splicing to intestinal pathogenesis has remained largely unexplored.In this project, we will use animal models to investigate the role of mRNA splicing for homeostasis and integrity of the intestinal epithelial barrier. We will also address whether perturbation in the regulation of mRNA splicing may precipitate the development of IBD or intestinal tumorigenesis. To evaluate the clinical relevance of the findings generated in the mouse models, we will perform translational studies using specimens from IBD and CRC patients.We anticipate that the planned translational investigations will not only extend our current knowledge of the role of mRNA alternative splicing for IEC homoeostasis and pathology, but they will also provide further insight on the mechanisms involved in the initiation or progression of IBD and CRC. Our study may also identify disease-specific gene isoforms and help evaluate their contribution to disease pathogenesis, as these isoforms may serve as biomarkers or therapeutic targets.
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