Forschung

The role of liver tertiary lymphoid structures in the progression of chronic biliary liver injury and hepatocarcinogenesis (Sofja Kovalevskaja-Preis der Alexander von Humboldt-Stiftung für Jun.-Prof. Dr. Veronika Lukacs-Kornek)

Die Leber erfüllt nicht nur im Stoffwechsel, sondern auch in der Immunabwehr vielfältige Aufgaben, die bislang wenig erforscht sind. Veronika Lukacs-Kornek verfolgt das Ziel, den Aufbau und die Funktion der Lymphgewebezellen in der Leber zu untersuchen und ihre Bedeutung für die Entstehung entzündlicher und chronischer Lebererkrankungen zu klären, die häufig zu Krebs führen. Ihre Forschung ist sehr relevant, da bisher für viele chronische Lebererkrankungen außer der Transplantation keine effektive Behandlung zur Verfügung steht. Jährlich sterben in Europa weit über 100.000 Menschen an einer Leberzirrhose, das Leberzellkarzinom ist einer der häufigsten bösartigen Tumore weltweit. Ein besseres Verständnis der immunologischen Funktionen, aber auch von Autoimmunerkrankungen der Leber könnte helfen, frühzeitig die Entwicklung und das Fortschreiten chronischer Lebererkrankungen zu verhindern.

Einsatz der transienten Elastographie als nicht-invasiver Marker für hepatisch bedingte Mortalität und Morbidität in der Nationalen Kohorte "NAKO" (Level 3-Projekt)

Liver cirrhosis is one of the main causes of death and disability-adjusted life-years worldwide. Generally, cirrhosis develops after a long period of liver-cell injury that leads to the deposition of collagen, leading to progressive fibrosis and nodule formation in the liver tissue. Most patients are diagnosed in late stages when liver decompensation or liver cancer develops. The diagnosis is rarely made in early stages-when liver fibrosis is mild to moderate but cirrhosis is not yet established-because the disease is asymptomatic. No strategies for detection of liver fibrosis at these early stages have been developed, but therapies are more effective in early stages than late stages of chronic liver diseases, so enabling early detection is an important research topic. Non-invasive methods for assessing liver fibrosis have been developed, of which the most commonly used are transient elastography-which estimates liver fibrosis by measuring liver stiffness-and serum biomarkers of fibrosis. Studies have shown that 6-7% of the adult population without known liver disease have liver fibrosis, mostly associated with non-alcoholic fatty liver disease. These data suggest that programmes of screening for liver fibrosis in the general population should be assessed.

COST Action BM0901 (SYSGENET): European Systems Genetics Network (2009-2013)

The main objective of the Action is to contribute to the discovery of gene networks that are involved in the development of complex genetic diseases in human. The main benefit of establishing SYSGENET will be at the scientific level. SYSGENET will allow researchers in different European countries to devise common research programmes and infrastructures which will give them access to various GRP resources from different European laboratories and to future GRP resources world-wide. The results from these research activities will provide the basis for a better understanding of human diseases and allow the development of new strategies for their prevention and therapy. In addition, SYSGENET will create a data sharing pan-European platform where the results of multiple phenotypic studies can be combined and new associations between phenotypes, gene networks and genotypes can be identified, allowing entering into the new area of systems genetics.

Virtuelles Helmholtz-Zentrum für Systemgenetik (GENESYS): Susceptibility to liver fibrogenesis (2007-2010)

Liver fibrogenesis, or scarring of the liver, is the common end-stage of chronic liver diseases, in particular after chronic viral infections, causing at least 10,000 deaths per year in Germany. In the past decade key molecular pathomechanisms of hepatic fibrogenesis due to chronic viral infections were identified: activated hepatic stellate cells (HSCs) drive the process of de novo deposition of abnormal extracellular matrix, which is modulated by complex interactions between cytokines, receptors, and matrix components.

Several studies demonstrated that the course and progression of the fibrogenic response to chronic liver injury display significant variability among individual patients. The marked variability of fibrosis progression has been attributed to aetiology, age, gender, and environmental factors. Host genetic factors are critical, but are yet to be identified systematically.

Recently, our group identified new genetic determinants of liver fibrogenesis by quantitative trait locus analysis in experimental crosses between fibrosis-susceptible and resistant mouse strains. A quantitative trait locus that confers susceptibility to hepatic fibrosis was refined by in silico mapping and, using congenic mice and transgenesis, the group demonstrated that the Hc gene (encoding complement factor C5) underlies this locus. Furthermore, common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in chronic inflammatory disorders and organ fibrogenesis across species. This study shows that the combination of current genomic technologies in the mouse can identify single small-risk genes in human.

We will study liver fibrogenesis in GRPs as a model for chronic liver injury secondary to viral infections, and map complex genetic traits that modulate gene expression and determine gene networks during liver fibrogenesis in GRPs. The project will be based on BXD RI strains.