|
|
Progesterone influence on the maternal immune system in pregnancy
Škvorová, Anna ; Koucký, Michal (advisor) ; Černý, Jan (referee)
Pregnancy represents a major challenge to the maternal immune system. From an immunological point of view, a fetus is a semi-allograft. The mechanisms providing immunological paradox of fetal tolerance are still not well known and require further research. A complex network of immuno-endocrine interactions ensures fetal growth and development within the maternal uterus. The hormone playing an indispensable role in pregnancy is progesterone. The aim of this thesis is to summarize current knowledge of the effects of progesterone on the immune system in pregnancy and its mechanisms. Progesterone can affect target cells via the classical nuclear progesterone receptors, which act as transcription factors, or it can act using a variety of other ways, including non-genomic rapid signaling. Progesterone optimizes conditions for successful establishment and maintenance of pregnancy, changes the amount, localization and characteristics of immune cells and production of cytokines. It reduces the antigen-presenting capacity of dendritic cells, monocytes, and macrophages, suppresses NK cell cytotoxicity, supports the proliferation of uterine NK and dendritic cells, affects B cells and induces the formation of T regulatory cells and their recruitment into the fetal-maternal interface. The wide range of...
|
|
|
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...
|
|
|
Antibody derivatives for the detection of human glutamate carboxypeptidase II
Bělousová, Nikola ; Bařinka, Cyril (advisor) ; Černý, Jan (referee)
Prostate cancer is the most common neoplasia in men. The therapy of progressed tumor is usually not efficient and early diagnosis is therefore crucial for successful treatment. Glutamate carboxypeptidase II (GCPII) is an established marker for prostate cancer imaging and therapy as the neoplastic transformation of prostate tissue is accompanied by the substantial increase of GCPII expression levels. Currently used GCPII-specific diagnostic and therapeutic reagents can be broadly categorized as small- molecule ligands or macromolecules. Antibodies are preferred macromolecules used in clinic. At the same time, however, protein engineering is regularly applied to modify natural antibodies to enhance their utility in biomedicine applications. This thesis summarizes the current knowledge about the GCPII structure and function and its role in diagnosis and therapy of prostate carcinoma. Powered by TCPDF (www.tcpdf.org)
|
|
|
Analysis of the resistence of B cell antigen receptor signaling to the inhibition of Src-family kinases
Borna, Šimon ; Brdička, Tomáš (advisor) ; Černý, Jan (referee)
Signalling through antigen specific receptors BCR and TCR is crucial for the development and the function of T cells and B cells. Although much is known about their signalling pathways a number of observations still remain to be clarified. In my thesis, I focused on the roles of Src-family kinases (SFKs) in the initiation of BCR- and TCR-mediated signalling. Several studies have suggested that in contrast to TCR signalling, BCR signal transduction could be initiated independently of SFKs or with only a minimal activity of these kinases. We used genetic approach to study the differences between TCR and BCR signalling apparatuses combined with inhibition of SFKs by pharmacological approach. Using this experimental set up, we show that the differences in the roles of SFKs and in the activities of SFKs needed for the initiation of BCR and TCR signalling are likely based on different composition or architecture of BCR and TCR. We further show that the SFK activity required for the initiation of TCR signalling is lower if ZAP-70 kinase is substituted with Syk kinase, which most likely reflects the different molecular mechanisms of Syk and ZAP-70 kinase activation. Key words: Src-family kinases, BCR receptor, TCR receptor, PP2, B cells, T cells, BCR signalling, TCR signalling.
|
|
|
mTOR mediated phosphorylation of Akt at Ser473 regulates cancer cell survival after severe hypertermia in PTEN-coordinated manner
Valentová, Iva ; Sadílková, Lenka (advisor) ; Černý, Jan (referee)
Hyperthermia (HT), a term used in general for temperatures higher than 42řC, induces cell stress response in dependence on its intensity, heating duration and target cell type (this is called a thermal dose). In vitro, HT causes changes in Ca2+ homeostasis as a consequence of endoplasmic reticulum stress and permeabilisation of the outer mitochondrial membrane. The release of cytochrom c further leads to activation of caspases that can result in cell death. In parallel, the presence of denatured proteins in the cell cytosol leads to the development of the so called unfolded protein response (UPR). UPR is characterized by increased expression and activation of molecular chaperones, increase in the intensity of proteosomal degradation and enhancement in autophagy. This process is accompanied by the attenuation of translation machinery, iniciation of DNA repair and activation of cytoprotective mechanisms leading to cell survival. This highly complex stress response mechanism is regulated mainly by the signalling pathways in the PI3K/Akt/mTOR axis. Cell survival is in the end fully dependent on the amount of energetic substrates, denatured proteins accumulation and on the level of irreversibly demaged DNA. If the termal dose is too high, the cell will ultimatively die. Hyperthermia is also one of the...
|
|
|
Historic causes and context of the present position of the Roman Catholic Church in the Czech society
Černý, Jan Karel ; Rychlík, Jan (advisor) ; Pehr, Michal (referee)
(in English) This thesis is focused on historic causes and context of contemporary position of the Roman Catholic Church in the Czech society. To chosen problematics I approach through a concept of spirituality which enables us to have a preview on other phenomena and processes that disrupted catholic religiosity. My thesis starts in the Enlightenment which has had a quite underlying ideological influence on the position churches all over the Europe, while I complemented this chapter by secularization aspects of Judeo-Christian tradition. The next chapter dedicating to 19. century is primarily focused on modernization processes (especially Czech nationalism) which could replace or suppressed traditional religiosity. The short 20. century is devided on formation of relationship between state, church and society (The First Republic and communist period) and simoustaneously in framework of this part it is introduced postmodern transformation of religion whose ,,offshoots" characterise present Czech spirituality. The Revolution and the beginning of the 90s are viewed from two approaches - from a dissolution of concensus and from adapted liminal theory. How it seems, the contemporary position of the Catholic Church is given profound processes - especially anti-catholic form of nationalism and a rate of...
|
|
|
Cell surface CD47 expression in cancer stem cell-targeted tumor therapy
Kuzmík, Ján ; Drbal, Karel (advisor) ; Černý, Jan (referee)
CD47 is a transmembrane glycoprotein with a high expression in both, healthy and cancer (stem) cells. Level of the CD47 expression is negatively correlated with survival of cancer patients. Binding of CD47 to SIRPα, localized on a phagocyte, triggers intracellular signaling cascade. The final effect of this cascade is dephosphorylation of nonmuscle myosin-IIA, which disrupts its function and accumulation to phagocytic synapse. The blockage of CD47-SIRPα signaling pathway in a presence of the pro-phagocytic signal induces phagocytosis of cancer cells. Afterwards, phagocytes can serve as the antigen presenting cells and prime T cell response. Role of CD47-SIRPα signaling pathway in immunity has established this pathway as a target of cancer therapy testing. Preclinical research has identified a positive therapeutic effect of blocking this signaling pathway. Nowadays, the first phase of clinical trials is being conducted. The most prevalent approach of blocking CD47-SIRPα signaling pathway in therapy is the use of anti-CD47 blocking monoclonal antibodies, which cause mild anemia. However, alternative approaches of blocking this pathway are also being developed. In this bachelor thesis, I have summarized the research related to the blockage of CD47-SIRPα signaling pathway as a cancer therapy.
|
|
|
The Role of Heat Shock Proteins in Pathogenesis of Placental Insufficinecy
Slabá, Kristýna ; Hromadníková, Ilona (advisor) ; Černý, Jan (referee)
Heat shock proteins (Hsp) are highly conserved proteins that are part of the universal stress response of the cell. Their main function is to protect cells against structural and functional damage. Organisms exposed to different forms of stress, such as e.g. a lack of nutrients or water, hypoxia, infection or inflammation, demonstrated an increased gene expression of these proteins. Pregnancy complications cause stress conditions for maternal and fetal organism, which may result in an increased gene expression of Hsp. In my thesis, I examined the concentration of extracellular mRNA for five different heat shock proteins (Hsp27, Hsp60, Hsp70, Hsp90, HspBP1) in the plasma of pregnant women and wheather this concentration is affected by possible pregnancy complications (preeclampsia, fetal growth restriction and gestational hypertension). I also investigated a possible correlation between mRNA plasma concentration for Hsp and pulsatility index values (PI) obtained by Doppler ultrasound. This research should help to invent a new predictive method for pregnancy complications, based on a detection of specific biomarkers in the first trimester of pregnancy. The research was conducted on plasma samples obtained from peripheral blood of pregnant women, whose collection was performed during clinical manifestations of...
|
|
|
Chimeric antigen receptors in the treatment of hematological malignacies
Fellnerová, Adéla ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Chimeric antigen receptors (CARs) are artificial molecules composed of an antibody derived antigen recognition domain which is fused with the signal transduction domain derived from the physiological TCR. CAR technology used to transduce patients T-cells and endow them with the specificity to a certain surface antigen, has been a major breakthrough in cancer immunotherapy in the last decade. This strategy has been most successful for treating hematologic malignancies. Various CAR approaches and applications are currently tested mainly in the United States where many clinical trials have been launched. In contrast, in the Czech Republic, there are only a few teams focused on this topic with no clinical trials going on. During my work on this diploma thesis and in close collaboration with MUDr. Pavel Otáhal, PhD., who is working on implementation of CAR technology into the Czech clinics for the treatment of B-cell malignancies, individual functional CARs were prepared and tested. CAR expressing Jurkat T-cell lines were generated using a lentiviral vector transduction system. CAR functionality was determined by two different assays. We have shown that individual CARs are able to recognize the B-cell lineage specific antigens CD19 and CD20 and significantly up-regulate the activation molecule CD69 upon...
|
|
|
Analysis of Memrane Proteins of Pathogenic Bacterim Francisella Tularensis
Schmidt, Monika ; Szotáková, Barbora (advisor) ; Černý, Jan (referee) ; Konopásek, Ivo (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate Mgr. Monika Schmidt Supervisor Doc. Ing. Barbora Szotáková, Ph.D. Title of Doctoral Thesis Analysis of membrane proteins of pathogenic bacterium Francisella tularensis Bacterium Francisella tularensis is highly infectious pathogen causing disease tularaemia. Due to the lack of standardization and little protection against highly virulent strains, the only vaccine developed against this pathogen is not allowed for clinical usage. Conserved hypothetical lipoprotein homological to thiol/disulfide oxidoreductase (DsbA) was recently described as essential virulence factor of Francisella tularensis. The dsbA gene deletion led to attenuation of the strain and development of immunoprotection. The DsbA protein sequence revealed the presence of carboxy-terminal DsbA_Com1-like domain harbouring the catalytic active site C-X-X-C and cis-proline and domain amino-terminal to FKBP type peptidyl-prolyl isomerase. This work was focused on functional a substrate characterization of DsbA protein. The functional analysis of this protein showed both the importance of the active site, cis-proline and the FKBP_N domain for the thiol/disulphide oxidoreductase activity. Further, this work also revealed the in...
|
guest ::
RSS feed.