Projektgruppe
Systemtoxikologie [SysTox]

LivTox

Junior Research Group Godoy

Our group has identified key molecular mechanisms mediating hepatocyte behavior in vitro (Godoy et al, Hepatology 2009 Jun;49(6):2031-43). These mechanisms, triggered in part by contact to 2D stiff matrix and inducing signaling pathways leading to Epithelial-Mesenchymal Transition (EMT), regulate the capacity of hepatocytes to perform important cellular functions such as proliferation, drug metabolism and resistance to cell death (Figure 1). Importantly, we discovered that the presence of a 3D soft extracellular matrix significantly improves in vivo-like behavior on cultured hepatocytes. However, these improved systems are far from fully reflecting the complexity of liver tissue, in part because the so-far discovered mechanisms governing hepatocyte dedifferentiation cannot account for the overall phenotype observed in vitro. A comprehensive understanding of molecular events involved in hepatocyte behavior in vitro and in vivo will yield the optimal conditions for improved methods for the evaluation of toxic substances which will spare experimental animals.

Our current lines of research include:

Improved in vitro systems for primary hepatocytes.
Our recent discoveries have identified signaling pathways and influence of ECM in hepatocytes behavior in vitro. We will further investigate these mechanisms using Gene Arrays, proteomics and state of the art confocal laser scanning microscopy (Figure 2). We will include the use of non-parenchymal cells and different ECM to further develop in vitro hepatocytes culture systems.

Consequences of EMT in liver damage and regeneration.
The responses of dedifferentiating hepatocytes in 2D matrixes indicate that a regenerating program might be responsible for the observed phenotype, including features of EMT. We will use animal models, including knock outs and siRNA technology, and state of the art molecular biology tools to fully characterize the role of EMT in liver damage and regeneration.

Role of cytokines in liver regeneration.
Recently we have identified novel cytokines and growth factors with potential important roles in liver regeneration. We will use in vitro and in vivo approaches to validate the role and mechanisms mediating the effects of these factors in liver response to toxicant damage and regeneration.

Group members

• Dr. Patricio Godoy (group leader)
• Dipl. Pharm. Markus Schug (PhD student)
• Dipl. Pharm. Gisela Campos (PhD student)
• Dipl. Vet. Seddik Hammad (PhD student)
• Mrs. Georgia Günther (scientific technical assistant)
• Mrs. Brigitte Begher-Tibbe (scientific technical assistant)

Networking and Colaborations:
Within IfADo: Prof. Jan G. Hengstler; Dr. Raymond Reif; Dr. Christoph van Thriel; Dr. Meinolf Blaszkewicz; Prof. Gisela Degen; Prof. Peter Roos.
Within Germany: Prof. Silvia Bulfone-Paus (Leibniz Zentrum für Medizin und Biowissenchaften, Borstel); Prof. Marino Zerial (Max Planck Institute für Molekulare Zellbiologie und Genetic, Dresden); Prof. Steven Dooley (Universitätsklinikum Mannheim, Mannheim); Prof. Albert Sickmann (Institute für Analytical Sciences, Dortmund).
International: Prof. Jan B. Hoek (Thomas Jefferson University, USA); Prof. Marco Arrese (Pontificia Universidad Católica de Chile, Chile).

Further selected publications.

1. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis.
Godoy P, Hengstler JG, Ilkavets I, Meyer C, Bachmann A, Müller A, Tuschl G, Mueller SO, Dooley S.
Hepatology. 2009 Jun;49(6):2031-43.

2. The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis.
Weng HL, Liu Y, Chen JL, Huang T, Xu LJ, Godoy P, Hu JH, Zhou C, Stickel F, Marx A, Bohle RM, Zimmer V, Lammert F, Mueller S, Gigou M, Samuel D, Mertens PR, Singer MV, Seitz HK, Dooley S.
Hepatology. 2009 Jul;50(1):230-43.

3. Dexamethasone-dependent versus independent markers of epithelial to mesenchymal transition in primary hepatocytes.
Godoy P, ...., Hengstler JG.
Biol. Chem. 2009 In press.

4. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice.
Hamzavi J, Ehnert S, Godoy P, Ciuclan L, Weng H, Mertens PR, Heuchel R, Dooley S.
J Cell Mol Med. 2008 Oct;12(5B):2130-44.

5. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice.
Hamzavi J, Ehnert S, Godoy P, Ciuclan L, Weng H, Mertens PR, Heuchel R, Dooley S.
J Cell Mol Med. 2008 Oct;12(5B):2130-44.

6. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage.
Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, Gebhardt R, Kanzler S, Geier A, Breitkopf K, Weng H, Mertens PR.
Gastroenterology. 2008 Aug;135(2):642-59.

7. Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes.
Weng HL, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, Kanzler S, Heuchel
R, Ueberham U, Gebhardt R, Breitkopf K, Dooley S.
Hepatology. 2007 Oct;46(4):1257-70.

8. Primary hepatocytes for systems biology approaches: a standardized in vitro system for for modeling of signal transduction pathways.
Klingmüller U,..., Godoy P, Hengstler JG.
Sys. Biol. (Stevenage) 2006 Nov;153(6):433-47.

9. TGF-beta/Smad signaling in the injured liver.
Breitkopf K, Godoy P, Ciuclan L, Singer MW, Dooley S.
Z Gastroenterol. 2006 Jan;44(1):57-66. (Review).