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Project properties

Title Altered resistance of "diseased" liver cells to cell death
Keywords cell death cholestasis fibrosis
Researchers prof.dr. A.J. Moshage
Type of projectOnbekend
Nature of the research Experimental research driven by a clinical problem. Techniques: cell biology; signal transduction; imaging; cell culture; gene modulation; siRNA
Fields of study cell biology gastroenterology
Background / introduction
Chronic liver diseases are characterized by the progressive loss of hepatocytes, the functional liver cells, as a result of cell death. Several toxic factors present in the chronically injured liver contribute to cell death, e.g. reactive oxygen species, pro-apoptotic cytokines like TNF and bile acids. Although the effects of these factors on NORMAL hepatocytes have been characterized in great detail, these studies do not reflect the clinical reality. Many liver diseases are characterized by cholestasis (accumulation of bile components in the liver) and/or steatosis (accumulation of lipids in hepatocytes). These cholestatic and/or steatotic hepatocytes respond differently to toxic factors than normal hepatocytes. In addition, any therapeutic intervention needs to be evaluated in these "diseased" hepatocytes. We have recently established in vitro models that mimick the "diseased" phenotype of hepatocytes in cholestatic and/or steatotic liver diseases. These models are important to evaluate the effects of toxic factors on signal transduction and cell death pathways in diseased hepatocytes, since they are a better reflection of the clinical reality.
Research question / problem definition
The goals of this project are to
1) elucidate the effects of relevant toxic factors present in the chronically injured liver
2) to determine the mechanism of cell death induced by these factors
3) to prevent cell death induced by these factors by manipulating signal transduction pathways.
The global outline of the whole project is to isolate hepatocytes from normal, steatotic (Zucker) rats and cholestatic rats (1 week bile duct ligation) and to compare:
1) The activation status of selected signal transduction intermediates
2) The sensitivity to various inducers of cell death
3) The effect of manipulaton of selected signal transduction pathways on the sensitivity to inducers of cell death

Hepatocytes isolated from normal, steatotic and cholestatic rats will be cultured and subjected to TNF, various forms of oxidative stress and bile acids. Effects on cell death (necrosis and apoptosis; mitochondrial function) will be analyzed. The role of various signal transduction pathways on cell death induced by these factors will be investigated using specific blockers for the JNK, p38, ERK1/2, Src-family, NF-kB and PI-3K pathways. In addition, the effect of anti-oxidants, adenoviral overexpression of HO-1 and insulin (resistance) on cell death will be investigated. Furthermore, we will explore the role of NADPH-induced ROS formation in hepatocyte death.
For more information on this research, including downloadable pdf-files of recent papers:
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