Thesis supervisor: Gyöngyi Szabó
Location of studies (in Hungarian): USA Abbreviation of location of studies: USA
Description of the research topic:
Description:
Non-alcoholic steatohepatitis (NASH), an increasingly common disease in the US, has common pathological features with alcoholic liver disease. Thus, it has been proposed that similar pathomechanisms may be involved. The role of lipopolysaccharide (LPS), a key endogenous activator of Kupffer-cell-mediated activation of inflammatory pathways in alcoholic steatohepatitis, is yet to be defined in NASH. LPS is recognized by the Toll-like receptor 4 (TLR4) and its co-receptors, CD14 and MD-2, expressed on the surface of immune cells and hepatocytes in the liver. Ligand-induced activation of TLR4 results in downstream signaling of the pro-inflammatory cascade after recruitment of the common TLR adapter molecule, MyD88, or in induction of type I interferons via recruitment of TRAM. Recruitment of inflammatory cells and increased pro-inflammatory cytokine production is associated with progression of NASH. This project will test the hypothesis that activation of the TLR4 receptor complex and TLR4-induced downstream signaling plays a role in development of inflammation and induction of fibrosis in NASH. Specifically, we will study whether the MyD88 common TLR adapter plays a role in NASH using a mouse model of NASH induced by feeding of a methionine-choline-deficient diet. Wild-type and MyD88-deficient mice will be used to evaluate development of steatosis, inflammation and liver damage by measuring specific serum and cytokines markers and transcription factor activation associated with steatosis and/or inflammation. THis project will also delineate the specific participation of bone-marrow-derived cells, particuarly Kupffer cells and hepatocyte in the development of steatosis and inflammations in NASH by using bone-marrow chimeras.
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