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The role of ADAM17 and other metalloproteases in liver pathological processes
Žbodáková, Oľga ; Sedláček, Radislav (advisor) ; Muchová, Lucie (referee) ; Stříšovský, Kvido (referee)
1 Abstract Liver fibrosis is a condition described by extensive accumulation of scar tissue in the liver. With further progression, it leads to cirrhosis or even to hepatocellular carcinoma. Liver fibrosis accompanies every chronic liver disease and its prevalence in adult European population is estimated to be around 4%. During my dissertation work, I studied the function of three members of Metzincin family of metalloproteinases - ADAM17, ADAM10 and MMP-19, in liver fibrosis and liver regeneration using mouse genetic models. ADAM17 and ADAM10 are important regulators of signalling pathways which are involved in immune response as well as differentiation. Both proteases are able to cleave ectodomains of their substrates from cell membrane, affecting bioavailability of ligands and functionality of receptors. Several of their substrates are involved in liver pathologies. MMP-19 on the other hand, is a metalloprotease mainly involved in extracellular matrix cleavage, important process in fibrosis development, as well as resolution of fibrosis. Our results demonstrate that ablation of ADAM10 results in increased susceptibility to liver fibrosis in mice, both spontaneous and toxin induced. ADAM10 deficiency affected biliary epithelium, as we detected higher markers of biliary damage in serum of ADAM10 deficient...
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Link between inflammation and cancer
Schierl, Jaroslav ; Poljaková, Jitka (advisor) ; Miarková, Eva (referee)
Chronic inflammation caused by many initiators can lead to a development of a tumor disease. Among these initiators, we found chronic infections as well as other biological, chemical or physical factors which have endogenous and exogenous origins as for example tobacco smoke, alcohol, radiation, obesity and others. The inflammatory response is orchestrated by immune system cells which contribute to a tumorigenesis by producing reactive oxygen and nitrogen species which harm cell structures, and by releasing cytokines - important mediators of inflammation - which increase cell proliferation and angiogenesis. But apart from higher risk of tumourigenesis due to chronic inflammation, the immune system cells also participate in tumor microenvironment formation. The main contributors are tumor associated macrophages, dendritic cells and T-cells. Besides other things, the complex tumor microenvironment is characterized by the presence of many inflammation mediators which assist in malignant cell proliferation, tumour progression and metastasis and angiogenesis. This bachelor thesis describes the key protumor and antitumor factors which are also involved in the inflammation process. These factors include proinflammatory cytokines, enzymes and transcription factors. The transcription factor NF-κB plays an...
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Mechanisms of specific immune response interactions with tumor cells.
Kaššák, Filip ; Hořejší, Václav (advisor) ; Černý, Jan (referee)
Interactions between the immune system and tumors have been among the highlights of present immunological research. An extensive body of new knowledge recently substantiated the long-presumed concept of cancer immunosurveillance. Immune system searches the organism for cells expressing tumor antigens or cellular stress signals and destroys them. T-cells, NK-cells and dendritic cells, as well as cytokine signaling and direct cell cytotoxicity play dominant role in this process. However, a fraction of nascent tumors can evade these mechanisms and create a dynamic equilibrium, gradually sculpting its phenotype by clonal selection. Eventually, tumor cells escape immune control by concealing themselves from recognition or by actively subjugating local immune response. This immunosubversion results in formation of immunosuppressive tumor microenvironment by recruiting protumorigenic cell populations, such as Treg cells, macrophages and myeloid derived suppressor cells. Soluble signaling molecules, as well as surface- expressed immune checkpoint molecules are exploited by tumor cells for inhibition of anti-tumor immunity. Highly effective therapeutic antibodies blocking these checkpoints have been developed for clinical use, with many more in current trials. Several other promising immunotherapeutic...
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