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Epigenetické regulace u autoimunitních onemocnění se zaměřením na revmatoidní artritidu
Horková, Veronika ; Daňková, Pavlína (advisor) ; Hušáková, Markéta (referee)
Exact cause of rheumatoid arthritis, as well as other autoimmune diseases has not been identified yet. In last twenty years, epigenetics showed a new face of immune system. DNA methylation, modification of histones - proteins around which DNA is wrapped, or interference of small RNA sequences - microRNAs, these all are heritable changes outside the DNA sequence that provide another component involved in autoimmunity. Presented epigenetic mechanisms alter gene expression and thus facilitate production of pro- inflammatory factors leading to autoimmune reactions. Moreover, genes regulating apoptosis are also frequently targeted by epigenetic modifications. Not only these mechanisms provide another level of immune defense, they also explain higher female susceptibility to autoimmune diseases and the influence of environment on pathogenesis of these diseases.
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Possible applications of polymeric nitric oxide donors in treatment of murine experimental tumors
Horková, Veronika ; Šírová, Milada (advisor) ; Krulová, Magdaléna (referee)
Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...
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Role of CD8- and CD4-Lck interactions in the signaling and development of T cells.
Horková, Veronika
Adaptive immune response plays a key role in maintaining homeostasis of the organism. T cells use an immense repertoire of T-cell receptors (TCRs) to discriminate between self and foreign antigens with very high sensitivity. Although we have many clues outlining how an ideal TCR repertoire is selected, and a good understanding of the TCR signaling machinery, there are still some key aspects of these processes that remain controversial. The objective of this thesis is to extend our knowledge of the very proximal events of TCR signaling, with special focus on interaction of TCR coreceptors with lymphocyte-specific kinase LCK. Coreceptor-LCK interaction has been described to regulate several aspects of T- cell development and response. We observed dynamic change of this interaction in course of T-cell development. Interestingly, CD4 and CD8 coreceptors displayed differential dynamics of interaction with LCK. Our data suggest that such disparity in coreceptor- LCK interaction leads to selection of more self-reactive TCR repertoire in CD8+ T cells. Moreover, when the highly self-reactive CD8+ T cells get to the periphery, the homeostatic signals drive their differentiation towards a more tolerogenic memory-like phenotype. To finally resolve the role of coreceptor-LCK interaction in the T-cell...
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Role of CD8- and CD4-Lck interactions in the signaling and development of T cells.
Horková, Veronika ; Štěpánek, Ondřej (advisor) ; Černý, Jan (referee) ; Hons, Miroslav (referee)
Adaptive immune response plays a key role in maintaining homeostasis of the organism. T cells use an immense repertoire of T-cell receptors (TCRs) to discriminate between self and foreign antigens with very high sensitivity. Although we have many clues outlining how an ideal TCR repertoire is selected, and a good understanding of the TCR signaling machinery, there are still some key aspects of these processes that remain controversial. The objective of this thesis is to extend our knowledge of the very proximal events of TCR signaling, with special focus on interaction of TCR coreceptors with lymphocyte-specific kinase LCK. Coreceptor-LCK interaction has been described to regulate several aspects of T- cell development and response. We observed dynamic change of this interaction in course of T-cell development. Interestingly, CD4 and CD8 coreceptors displayed differential dynamics of interaction with LCK. Our data suggest that such disparity in coreceptor- LCK interaction leads to selection of more self-reactive TCR repertoire in CD8+ T cells. Moreover, when the highly self-reactive CD8+ T cells get to the periphery, the homeostatic signals drive their differentiation towards a more tolerogenic memory-like phenotype. To finally resolve the role of coreceptor-LCK interaction in the T-cell...
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Possible applications of polymeric nitric oxide donors in treatment of murine experimental tumors
Horková, Veronika ; Šírová, Milada (advisor) ; Krulová, Magdaléna (referee)
Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...
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Epigenetické regulace u autoimunitních onemocnění se zaměřením na revmatoidní artritidu
Horková, Veronika ; Daňková, Pavlína (advisor) ; Hušáková, Markéta (referee)
Exact cause of rheumatoid arthritis, as well as other autoimmune diseases has not been identified yet. In last twenty years, epigenetics showed a new face of immune system. DNA methylation, modification of histones - proteins around which DNA is wrapped, or interference of small RNA sequences - microRNAs, these all are heritable changes outside the DNA sequence that provide another component involved in autoimmunity. Presented epigenetic mechanisms alter gene expression and thus facilitate production of pro- inflammatory factors leading to autoimmune reactions. Moreover, genes regulating apoptosis are also frequently targeted by epigenetic modifications. Not only these mechanisms provide another level of immune defense, they also explain higher female susceptibility to autoimmune diseases and the influence of environment on pathogenesis of these diseases.
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