PORTEFEUILLE

Aim of the project is to test whether JNK1 and JNK2 (c-Jun N-termina kinases) have essential functions in the liver. Mice and liver cells lacking JNK1, JNK2 or any JNK activity will be subjected to defined stimuli of hepatocyte proliferatoon, apoptosis and call injury. Specific in vitro and in vivo experiments may identify JNKs as crucial components of signal transduction cascades which control heptocyte functions during physiological and disease conditions.

Liver cell apoptosis represents a common mechanism of liver cell damage in many liver diseases and liver cell proliferation is essential for liver regeneration after infectious and toxic injury, partial resection and transplantation. The signal transduction pathways which control these cell processes are incompletely understood. The results of the planned work may establish an essential function for the Jnks in the regulation of liver cell survival, apoptosis and proliferation and by that may identify Jnks as potential targets for the development of novel therapeutic strategies.

To inhibit Jnk acitivity in hepatocytes, mice expressing a dominant-negative mutant of Jnk1 (dnJnk1) were generated using two different hepatocyte-specific expression vectors (Alb/aFP-dnJnk1, TTR-dnJnk1). For both constructs, transgene positive founder mice were obtained, which expressed dnJNK1 mRNA in the liver. To test for inhibition of the Jnk pathway, partial hepatectomy was performed. In none of 11 analysed lines, transgene expression was associated with efficient inhibition of the Jnk pathway in the liver. Liver regeneration after partial hepatectomy was comparable between Jnk1 mutant, Jnk2 mutant and wildtype mice. In both Jnk1 and Jnk2 mutant mice, apoptosis was efficiently induced by Fas antibody or TNFa treatment.

Selzner N, Selzner M, Jochum W, Graf R, Ammann-Vesti B, Clavien PA (2006) Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J Hepatol, 44:694-701
Tian Y, Jochum W, Georgiev P, Moritz W, Graf R, Clavien PA (2006). Kupffer cell-dependent TNF- signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse. Proc Natl Acad Sci U S A, 103:4598-603
Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA (2006) Platelet-derived serotonin mediates liver regeneration.
Science, 312: 104-107
Hoekstra H, Porte RJ, Tian Y, Jochum W, Stieger B, Moritz W, Slooff MJ, Graf R, Clavien PA (2006) Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice. Hepatology; 43:1022-1031
Heinrich S, Jochum W, Graf R, Clavien PA (2006) Portal vein ligation and partial hepatectomy differentially influence growth of intrahepatic metastasis and liver regeneration in mice. J Hepatol, 45:35-42
Georgiev P, Navarini AA, Eloranta JJ, Lang KS, Kullak-Ublick GA, Nocito A, Dahm F, Jochum W, Graf R, Clavien PA (2007) Cholestasis protects the liver from ischaemic injury and post-ischaemic inflammation in the mouse. Gut, 56:121-128
Nocito A, Georgiev P, Dahm F, Jochum W, Bader M, Graf R, Clavien PA (2007). Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice. Hepatology, 45:369-376
Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, Renner EL, Clavien PA (2007) Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology, 133:608-618
Georgiev P*, Jochum W*, Heinrich S, Jang JH, Nocito A, Dahm F, Graf R, Clavien PA (2008) Characterization of time-related changes after bile duct ligation in mice - a new look at an old model. Br J Surg, 95:646-656 (* Gemeinsame Erstautoren)
Hoekstra H, Tian Y, Jochum W, Stieger B, Graf R, Porte RJ, Clavien PA (2008). Dearterialization of the liver causes intrahepatic cholestasis due to reduced bile transporter expression. Transplantation, 85:1159-1066
Furrer K, Tian Y, Pfammatter T, Jochum W, El-Badry AM, Graf R, Clavien PA (2008). Selective portal vein embolization and ligation trigger different regenerative responses in the rat Liver. Hepatology, Epub ahead of print
Nocito A, Dahm F, Jochum W, Jang JH , Georgiev P, Bader M , Graf R, Clavien PA (2008) Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts. Cancer Res, accepted for publication

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