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Role of the Bcl-2 homolog Bim in T cell-mediated liver immunopathology

English title Role of the Bcl-2 homolog Bim in T cell-mediated liver immunopathology
Applicant Corazza Nadia
Number 120427
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.07.2008 - 29.02.2012
Approved amount 243'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (6)

immune system; liver immunopathology; Bcl-2 homolog Bim; death ligands; hepatocyte apoptosis; LCMV

Lay Summary (English)

Lead
Lay summary
The liver occupies a watershed position between the gastrointestinal and systemic venous circulations, and one of its several functions is to filter the blood. Thus this organ is constantly exposed to several external compounds, potential pathogens and food derived antigen entering the gut and several drug metabolites and toxins from the blood system. For these reasons the liver has developed on one hand a complex and particular immune system able to mount rapid immune response again potential dangerous antigen without leading damage of the organ and, on the other hand complex apoptosis mechanisms of hepatocytes to render them less susceptible to potential damage. The consequences of uncontrolled inflammatory immune responses have been illustrated during the pathogenesis of different liver diseases such as hepatitis. For these reasons complex apoptosis mechanisms exist in the liver from both target and effector sites, first to avoid uncontrolled hepatocytes apoptosis and second to control expansion and retraction of activated T cells and as a consequence liver disease.It is to presume that in the liver the mechanisms involved in effector cell (i.e. activated T cells) and target cell apoptosis are regulated differently compared to other tissues less exposed to potential dangerous compounds. For instance, in contrast to normal cells in which Fas triggering directly induces the activation of caspases and subsequently apoptosis, hepatocytes require the amplification of the signal via Bcl-2 homologs Bim and Bid inducing activation of the mitochondria pathway. We hypothesize that firstly, Bim is likely not to be limited to the Fas signaling pathway, but may extend to other death ligand as well as different drug apoptosis triggers involving the mitochondrial pathway. Secondly, since mice deficient in Fas pathway as well as Bim deficient mice showed impaired peripheral deletion during immune resolution, we hypothesize that this two apoptosis pathways represent mediators of the very similar apoptosis mechanism not only in hepatocytes but also in activated T cells.The aim of this proposal is to understand the role of Bcl-2 homolog Bim in T cell-mediated liver immunopathology. In particular the two specific goals of this project can be summarized as follow: i) role of Bim in hepatocytes apoptosis induced by extrinsic and intrinsic apoptosis triggers, in vitro and in vivo and ii) the role of Bim and its interaction with other death ligands in T cell mediated liver disease.To answer these specific questions, a variety of in vitro and in vivo assays will be employed. We will use ex vivo isolated hepatocytes from different mice strain to study the respective role of different apoptosis mediators as well as their interactions in hepatocytes cell death. In particular for this purpose apoptosis assays and biochemical analysis of the intracellular events involved in these apoptosis processes will be performed. In parallel we will do in vivo experiments assessing the role of Bim in T cell mediated liver disease. For this purpose we will use the lymphocytic choriomeningitis virus (LCMV) transfer model of liver infection. Using this model we will be able to define the role of Bim and its interaction with death ligands in the retraction phase of activated T cells during viral liver infection and the consequence on disease development.With the discovery of the involvement of Bim in Fas/FasL mediated hepatocytes apoptosis we have identified a novel apoptosis mechanism to modulate hepatocytes apoptosis. However, Bim mediated modulation of hepatocytes apoptosis is likely not to be limited to Fas signaling pathway, but may extend to other apoptosis triggers involving the mitochondrial pathway. The careful and in-depth analysis of the role of Bim in hepatocytes apoptosis induced by extrinsic and intrinsic triggers, in vitro and in vivo and ii) the role of Bim
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The Proapoptotic Bcl-2 Family Member Bim Plays a Central Role during the Development of Virus-Induced Hepatitis.
Lauer Christoph, Brunner Thomas, Corazza Nadia (2012), The Proapoptotic Bcl-2 Family Member Bim Plays a Central Role during the Development of Virus-Induced Hepatitis., in Journal of immunology (Baltimore, Md. : 1950), 188(2), 916-22.
Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage.
Badmann A, Keough A, Kaufmann T, Bouillet P, Brunner T, Corazza N (2011), Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage., in Cell death & disease, 2, 171-171.
Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner.
Schmich Kathrin, Schlatter Rebekka, Corazza Nadia, Sá Ferreira Karine, Ederer Michael, Brunner Thomas, Borner Christoph, Merfort Irmgard (2011), Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner., in Hepatology (Baltimore, Md.), 53(1), 282-92.
Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid.
Schneider-Jakob S, Corazza N, Badmann A, Sidler D, Stuber-Roos R, Keogh A, Frese S, Tschan M, Brunner T (2010), Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid., in Cell death & disease, 1, 86-86.
Immune cell-mediated liver injury.
Corazza Nadia, Badmann Anastasia, Lauer Christoph (2009), Immune cell-mediated liver injury., in Seminars in immunopathology, 31(2), 267-77.
Distinct but complementary roles of Fas ligand and Bim in homeostatic T cell apoptosis.
Kassahn Daniela, Brunner Thomas, Corazza Nadia (2008), Distinct but complementary roles of Fas ligand and Bim in homeostatic T cell apoptosis., in Cell cycle (Georgetown, Tex.), 7(21), 3469-71.

Scientific events



Self-organised

Title Date Place
Training Course on “Concepts and Methods in Programmed Cell Death” 29.09.2010 Bern

Awards

Title Year
Eduard-Adolf-Stein-Preis 2009

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