Research Programmes
Do you know…
- … the scientists in CEITEC will be researching what happens in the brain when a human has realized that they have made a mistake?
- … there will be nearly 800 scientists in CEITEC?
- … in CEITEC we will be researching how the brain works and why some people are motivated and others are not?
- … thanks to CEITEC most of the diagnostic methods will be cheaper, faster and more comfortable for the patients?
- … 63 research teams will be created in CEITEC?
- … there will be 7 research programmes in CEITEC?
- … there will be more than 1,000 modern instruments in CEITEC?
- … more than 31,000 m2 of new infrastructure will be built in CEITEC?
- … more than 1,500 students will use the CEITEC infrastructure per year?
- … there will be 10 shared laboratories created in CEITEC?
- … CEITEC has 6 partners?
- … work will be carried out on self-cleaning surfaces in CEITEC?
- … CEITEC will co-operate closely with the industrial sector?
- … there will also be international scientists working in CEITEC?
- … CEITEC will support the international mobility of scientists?
- … the scientists in CEITEC are developing a subdermal chip which will analyse some life functions and will inform doctors from a distance?
- … the scientists in CEITEC are working on the development of a device which will enable physiotherapy from a distance?
- … the scientists at CEITEC are working on the development of biosensors?
- … CEITEC will be created in the south-Moravian city of Brno?
Molecular Gastroenterology and Hepatology
THEMATIC RESEARCH FOCUS
RESEARCH AREAS
- Role of intermediate filaments in digestive organs
- Pathogenesis and significance of Mallory-Denk bodies
- Role of hepcidin in health and disease
MAIN OBJECTIVES
- To define the importance of intermediate filaments in digestive organs. This will be done by combination of human association studies as well as studies in transgenic mouse models and primary cell cultures. The focus will be on the role of keratins 8 and 18 in liver disease, particularly non-alcoholic fatty liver disease and drug-induced liver injury.
- To delineate the pathogenesis and significance of Mallory-Denk bodies (MDB). In a mouse model of MDB formation, we will explore the importance of protein misfolding and degradation mechanisms in the aggregate formation. Human liver biopsy specimen will be used to validate findings from a rodent model. Isolation of MDBs by laser capture microscopy or gradient centrifugation will be employed to further characterize MDB composition.
- To study the role of hepcidin in health and disease. Hepcidin knockout animals will be used to further dissect the consequences of iron overload. Crossbreeding with additional transgenic mice will enable us to study the impact of improper iron distribution. Hepcidin ELISA will be used to determine hepcidin synthesis in selected human diseases.
CONTENT OF RESEARCH
Animal model as a tool towards the understanding of digestive disorders
Our goal is to improve our understanding of specific human digestive diseases. Mouse models mimicking the development of these disorders are the primary tool to reach this goal. Several experimental mouse models have already been established including models of acute acetaminophen- or apoptosis-related liver toxicity, liver fibrosis development (carbon tetrachloride/thioacetamide injection, bile duct ligation), iron overload or Mallory-Denk body formation. In addition, we are currently investigating the pathomechanisms of acute experimental pancreatitis (caerulein) and murine colitis (dextran sulphate sodium). The above-described tools are employed to test the impact of selected human-related genetic changes (such as single nucleotide polymorphisms in keratins) or other conditions (iron-overload caused by downregulation of hepcidin expression) in disease development. To that end, we are using multiple transgenic mouse lines, which are either commercially available; are provided by our collaborators or are currently produced in our own lab. The results from animal experiments are further validated in primary cell cultures and are compared to the human findings. To obtain the latter, we are performing human association studies assessing the role of genetic variants in selected human pathologies (such as alcoholic liver disease, drug-induced liver injury and others). Gene profiling is used to detect expression changes associated with specific conditions (such as presence of MDBs) and to find candidate genes for further rodent experiments.
KEY RESEARCH EQUIPMENT
PLANED RESEARCH INFRASTRUCTURE
Core Facility
The research group will be one of the principal users of the equipment available within CEITEC Genomics Core Facility.
CURRENT RESEARCH INFRASTRUCTURE
- Nucleic acid analysis: devices for PCR, qPCR, DNA electrophoresis and high-throughput mutation screening via dHPLC.
- Protein analysis: SDS-PAGE and Western blotting apparatus, ultracentrifuge for cell fractionation, 2D gel apparatus.
- Histology / immunohistochemistry: equipment for generation / cutting of paraffin blocks and cryo-sections, fluorescence and transmitted light microscope with an attached documentation system.
- Animal experiments: equipment for inhalative anesthesia and primary hepatocyte cell culture.
- DNA sequencing as well as equipment serving mainly for research tasks such as microarray scanners (short and long oligonucleotide platforms) or nucleofector.
MAIN PROJECTS
- Characterisation of the significance of intermediate filaments in stellate cells and enteric glia cells (TUR 09/I22), Internationales Buro of German Ministry of Education and Research (BMBF), 2009-2012, Pavel Strnad.
- The importance of keratin overexpression in the liver (STR 1095/4-1), German research foundation (DFG), 2011-2014, Pavel Strnad.
- Einfluss von Chaperonen und oxidativem Stress auf Mallorykorperentstehung (STR 1095/1-1), German research foundation (DFG), 2008-2011, Pavel Strnad.
- Genesis and consequences of inborn and acquired alterations of hepatocellular keratin architecture (STR 1095/2-1), German research foundation (DFG) (Emmy Noether programme), 2009-2014, Pavel Strnad.
SELECTED PUBLICATIONS
- STRNAD, P., ZHOU, Q., HANADA, S., LAZZERONI, L., C., ZHONG, B., SO, P., DAVERN, T., J., LEE, W., M., OMARY, M., B. Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations. Gastroenterology. 2010, 139, p. 828-835.
- STRNAD, P., TAO, G., Z., ZHOU, Q., HARADA, M., TOIVOLA, D., M., BRUNT, E., M., OMARY, M., B. Keratin mutation predisposes to mouse liver fibrosis and unmasks differential effects of the CCl4 and thioacetamide models. Gastroenterology. 2008, 134, p. 1169-1179.
- STRNAD, P., TAO, G., Z., SO, P., LAU, K., SCHILLING, J., WEI, Y., LIAO, J., OMARY, M., B. “Toxic memory“ via chaperone modification is a potential mechanism for rapid Mallory-Denk body induction. Hepatology. 2008, 48, p. 931-942.
- STRNAD, P., HARADA, M., SIEGEL, M., TERKELTAUB, R., A., GRAHAM, R., M., KHOSLA, C., OMARY, M., B. Transglutaminase-2 regulates Mallory body inclusion formation and injury associated liver hypertrophy. Gastroenterology. 2007, 132, p. 1515-1526.
- STRNAD, P., LIENAU, T., C., TAO, G., Z., LAZZERONI, L., STICKEL, F., SCHUPPAN, D., OMARY, M., B. Keratin variants associate with fibrosis and inflammation progression during chronic hepatitis C infection. Hepatology. 2006, 43, p. 1354-1363.
- RUCKOVA, E., et al. Role of alternative telomere lengthening unmasked in telomerase knock-out mutant plants. Plant Molecular Biology. 2008, 66(6), p. 637-646.
EUROPEAN UNION
