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Mechanisms of apoptosis-induced proliferation and regeneration in the intestinal tract: Implications for the pathogenesis of inflammatory bowel diseases (IBD) and intestinal carcinogenesis

English title Mechanisms of apoptosis-induced proliferation and regeneration in the intestinal tract: Implications for the pathogenesis of inflammatory bowel diseases (IBD) and intestinal carcinogenesis
Applicant Weber Achim
Number 146940
Funding scheme Project funding (Div. I-III)
Research institution Institut für Klinische Pathologie Departement für Pathologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.05.2013 - 31.03.2017
Approved amount 343'960.00
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Keywords (4)

colon cancer; inflammatory bowel disease; intestinal tract; cell death

Lay Summary (German)

Lead
Chronisch entzündliche Darmerkrankungen (CED; Colitis ulcerosa und Morbus Crohn) und Darmkrebs sind in Ländern der westlichen Welt häufige, für die Betroffenen schwerwiegende Erkrankungen. Auch wenn einzelne Schritte der Pathogenese der CED und der Darmkrebsentstehung gut beschrieben sind, so ist die zeitliche Abfolge und das genaue Zusammenspiel der krankheitsrelevanten Faktoren wie Genetik, Diät, Darmflora, Entzündung etc. nicht vollständig verstanden
Lay summary

Unser übergeordnetes Ziel ist das Verständnis der Rolle des „induzierten Zelltods“ (der sog. Apoptose) von Darmzellen, der in Folge verschiedenartiger Schädigung auftritt, bei der Entstehung der CED und von Darmkrebs. Dazu werden genetisch modifizierte Mäuse untersucht, die eine erhöhte Rate von „induziertem Zelltod“ in der Darmschleimhaut aufweisen und sekundär eine chronische Entzündung und permanente Regeneration entwickeln. Durch Manipulation verschiedener Immunzellen der Mäuse soll jeweils deren Einfluss auf die Entzündung und Regeneration untersucht werden. Wir möchten die Vermutung überprüfen, dass die sich steigernde Abfolge von Zelltod und Regeneration in der Darmschleimhaut zur Entstehung von Darmkrebs führt, und dass diese Abfolge durch Veränderungen im Immunsystem der Mäuse beeinflusst werden kann. Ziel ist es, aus diesen Arbeiten Erkenntnisse zur therapeutischen Beeinflussbarkeit der CED und des Darmkrebses zu gewinnen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Von diesem neuartigen, der menschlichen CED und dem Darmkrebs sehr ähnlichen Mausmodell erwarten wir Erkenntnisse zur Pathophysiologie der CED und der Darmkrebsentstehung und die Möglichkeit, therapeutische Ansätze zu testen.

 

Key words

Intestinal tract, cell death, inflammatory bowel disease, colon cancer

Direct link to Lay Summary Last update: 14.06.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Bcl-xL is an oncogenic driver in colorectal cancer
Anna-Lena Scherr (2016), Bcl-xL is an oncogenic driver in colorectal cancer, in Cell Death and Disease, 7(e2342), 1-10.
Mitochondrial function controls intestinal
Berger Emanuel (2016), Mitochondrial function controls intestinal, in Nature Communications, 7(13171), 1-17.
Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists
Soldini Davide (2014), Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists, in Journal of Clinical Pathology, 67, 582-586.

Collaboration

Group / person Country
Types of collaboration
Christoph Klose United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Mathias Heikenwälder Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Kristian Unger Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Bruno Köhler Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Owen J. Sansom Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Andrew Macpherson, Department of Gastroenterology, Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Key Stone Symposion on Cell Death and Inflammation , Dublin, Ireland Poster MCL-1 ensures intestinal mucosal integrity and protects against WNT-driven carcinogenesis 31.05.2017 Dublin, Ireland Heikenwälder Mathias; Weber Achim; Honcharova-Biletska Hanna; Böge Yannick;


Associated projects

Number Title Start Funding scheme
130822 Zelluläre und genetische Mechanismen der Entwicklung von hepatozellulären Karzinomen bei chronischer Hepatitis am Mausmodell und Validierung an humanen Leberproben. 01.04.2010 Project funding (Div. I-III)
182764 Mechanisms of tissues homeostasis and tumor suppression by MCL-1 01.06.2019 Project funding (Div. I-III)

Abstract

Intestinal, in particular colorectal carcinoma is a common and frequently lethal cancer. Although the etiology is largely unclear, it is known that both, environmental as well as genetic factors influence intestinal tumor development. Patients with inflammatory bowel disease (IBD), suffering from chronic intestinal mucosal inflammation and mucosal damage, are at higher risk to develop intestinal carcinomas. As in general when studying human diseases, the availability of appropriate animal models which closely recapitulate the human disease is also a prerequisite for studying IBD and intestinal tumorigenesis and allowing interventional studies for the development of therapeutic strategies.Performing an IEC (intestinal epithelial cells)-specific knock-out of the anti-apoptotic gene myeloid cell leukemia-1 (mcl-1), we created a novel mouse model (Mcl-1DeltaIEC mice) which spontaneously, i.e. without chemical challenge or other manipulations, reveals the morphologic hallmarks of IBD, i.e. the side-by-side occurrence of intestinal mucosal damage and chronic bowel inflammation with changes in the cytokine and chemokine profile as well as alterations in innate and adaptive immune cells in the lamina propria. Furthermore, Mcl-1DeltaIEC mice eventually develop intestinal tumors including invasive carcinomas. In this project, we aim to study crucial aspects of IBD pathogenesis and intestinal carcinogenesis by further characterizing Mcl-1DeltaIEC mice and performing interventional studies. For this purpose, at first the intestinal phenotype of Mcl-1DeltaIEC mice is further characterized morphologically (histology, special and immune stains), on molecular level (gene expression studies) and by immunological methods (immune stains, lamina propria FACS). Tumors developing in the small and large bowel of Mcl-1DeltaIEC mice are analyzed on morphologic (histology, special and immune stains) and molecular (gene expression studies, array-comparative genomic hybridization (aCGH), mutational analysis) level. The role of immune cells in the interplay of tissue destruction and inflammation is determined by crossing Mcl-1DeltaIEC mice to RAG-1-/- mice deficient of mature lymphocytes, as well as by depletion of monozytes, granulozytes or dendritic cells . The role of macrophages and dendritic cells is investigated in the early phase of intestinal pathology development (8 weeks of age) of Mcl-1DeltaIEC mice when already clear changes in the systemic and local cytokine and chemokine expression pattern and also adenomas are detected. To this aim, macrophages (e.g. chlodronate) or dendritic cells (CD11ci DTR mice) are depleted at 4 to 8 weeks of age in Mcl-1DeltaIEC, and various parameters (e.g. cytokine expression pattern) are analyzed. The role of intestinal microbiota in tissue destruction and inflammation is studied by keeping Mcl-1DeltaIEC mice under germ-free conditions. The significance of findings obtained for the Mcl-1DeltaIEC model in the different subprojects is verified in comparative studies on gene expression patterns and immune cell composition in human tissues from IBD patients as well as on gene expression patterns and genetic changes in patients with intestinal tumors, respectively.In summary, results obtained in this project shall help us to understand the role of epithelial damage and immune cells in the pathogenesis of both, human IBD and intestinal carcinogenesis. Further, we prospect that data of these experiments will contribute to understand the currently evolving concept of apoptosis-induced proliferation and carcinogenesis. Finally, we assume to provide sufficient evidence showing that the Mcl-1DeltaIEC model is an appropriate tool for interventional studies on IBD and intestinal carcinogenesis.
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