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Role of PARs and other biomarkers in the diagnosis of lung and neurodegenerative diseases
Brůžová, Magdalena ; Matěj, Radoslav (advisor) ; Němejcová, Kristýna (referee) ; Škarda, Jozef (referee)
1 SUMMARY In recent years, biomarker research has been the subject of many studies that address the etiopathogenetic processes of various diseases. Finding a biomarker that reflects the pathological processes of the disease with high sensitivity and specificity and was easily available and stable, would greatly facilitate the diagnosis of those diseases that are not easy to distinguish by conventional screening methods. Interstitial lung diseases (ILDs) include a heterogeneous group of disorders mostly of inflammatory nature. The resulting damage of the lung parenchyma can lead to its remodeling and fibrotization. The fibroproliferative process in different types of ILDs can result in similar clinical manifestations and findings on radiological images and biopsy specimens, which makes differential diagnosis difficult. Therefore, research in this area focuses on the presence of biomarkers in bronchoalveolar lavage fluid (BALF) to determine biomarker levels specific to individual ILDs. BALF analysis is used for differential diagnosis of patients with ILDs, but it can also be used to monitor the course of the disease, or response to the treatment. In our first study, we compared the levels of biomarkers in BALF in patients with sarcoidosis and hypersensitivity pneumonia (HP). From the results of the study, it...
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The role of proteinases-activatable receptor - 2 (PAR-2) in pathogenesis of human disease
Matěj, Radoslav ; Mandys, Václav (advisor) ; Fakan, František (referee) ; Ehrmann, Jiří (referee) ; Rudolf, Emil (referee)
It was presented that one of the pancreatic enzymes, trypsin, modulates many biological processes by acting on specific proteinase-activated receptor 2 (PAR-2). PAR-2 belongs to a family of G protein coupled receptors activated by tethered ligand sequences within the N-terminal, which is made accessible after the site-specific cleavage of the protein. Trypsin activates PAR-2 by the mediation of a unique process inhering in the recognition of the receptor by enzyme, subsequent c1eavage at the specific site ofNH2-terminal and presentation of a new NH2 terminal, which behaves as a tethered ligand. This ligand interacts with the extracellular doma in of receptor molecule. Thus, P AR-2 is a receptor, whose I igand is a physical part of the receptor molecule. This receptor was previously described on norma I as well as ma lignant immunocompetent cells, on endothelial and muscle cells of major as well as minor vessels. Its presence was also immunohistochemically demonstrated on intestinal epithelial cells, epithcl ial cells of exocrine organs, keratinocytes, fibroblasts and other cell types in stomach, small intestine, colon, liver and kidney. PAR-2 is expressed on various cells with a wide spectrum of cellular responses after activation. ln the firs t part of th is work we focused on the role of PAR-2 dUl·ing the...
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Molecular genetic aspects of neurodegenerative diseases
Parobková, Eva ; Matěj, Radoslav (advisor) ; Kalinová, Markéta (referee) ; Menšíková, Kateřina (referee)
Genetics plays a crucial role in translational research, which ultimately aims to develop new therapies that modify neurodegenerative disorders. We anticipate that individual genetic profiling will become increasingly important in a clinical context with implications for patient care in line with the proposed ideal of personalized medicine. Although whole exome sequencing (WES) is now widely used in gene identification studies, there is no doubt that whole genome sequencing (WGS) will soon replace WES as the standard method for gene discovery. Hopefully, in the near future, comparable initiatives will be developed to generate global, fully genomic, publicly available data for various forms of neurodegenerative diseases such as FTD. In the first part of this work we focused on a group of patients diagnosed with "pure" sCJD and sCJD and PART or early phase AD and sCJD with more advanced AD. We compared and analyzed a new generation sequencing (NGS) method of 15 genes that may be involved in the development of the disease. We identified a p.E318G polymorphism in the PSEN1 gene, which was found in three patients (10.3%), one of whom had pure sCJD and two were sCJD + AD. No relevant variants were observed for the other AD APP and PSEN2 genes. In PRNP, insertion of p.P84_Q91Q was detected in one patient...
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Role of proteinase-activated receptor 2 in pathogeneiss of neurodegenerative diseases
Rohan, Zdeněk ; Matěj, Radoslav (advisor) ; Hermanová, Markéta (referee) ; Dundr, Pavel (referee)
This Thesis discusses the complex topic of the role of proteinase-activated receptors (PARs) in the physiology and pathophysiology of central nervous system diseases, and to some extent, the role of PARs in cancer pathobiology. Based on the results from this Thesis, we can conclude that PAR2 levels in the CSF do not track neuronal damage; therefore, PAR2 cannot be used as a marker of neuronal damage. Expression and activity of PAR2 in the brain appears to be mostly related to the activity of the disease process itself. To study the role of PAR2 in neurodegenerative diseases characterized by white matter and oligodendrocyte degeneration, a precise morphological descritption of individual diseases is essential. In the study aimed pathology of motor neuron disease we found reactive incre- ase in oligodendrocyte density in corticospinal tracts in reaction to white matter damage. In other study we confirmed the existence of a new variant of multiple system atrophy, atypical MSA (aMSA) charcterized by specific degenration of hippocampal neurons. Since the activity of kallikrein 6-PAR2 axis attenuates α-synuclein aggregation, its deficiency in hippocampus may be a prerequisite for its dominant degeneration leading to the develop- mant of α-synuclein neuronal inclusions and aMSA phenotype. Regarding the...
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The characterization of blood platelet cellular prion protein
Broučková, Adéla ; Holada, Karel (advisor) ; Matěj, Radoslav (referee) ; Suttnar, Jiří (referee)
The conformational conversion of the cellular prion protein (PrPc) to the misfolded isoform (PrPsc) is the central pathogenic event in the transmissible neurodegenerative prion diseases. The recently shown transmissibility of variant Creutzfeldt-Jakob disease by blood transfusion emphasizes the need for better understanding of the PrPc in blood. In the current thesis, we focused on blood platelet PrPc, which has not been very well described so far. In the first part of the thesis, platelet PrPc was characterized as glycosylphosphatidylinositol- anchored glycoprotein with dominant diglycosylated form. Platelet PrPc was shown to be sensitive to cleavage with proteinase K, which is a feature discriminating between cellular and pathological prion protein. We have confirmed that platelet PrPc binds copper ions by its N- terminal octapeptide repeat region. Regarding quantity of PrPc molecules expressed on blood elements we have proved that both platelets and red blood cells express considerable amount of PrPc and thus can not be neglected in the problematic of prions transmission by blood transfusion. The detailed study regarding PrPc localization in blood platelets is presented in the second part of the thesis. PrPc was shown to be expressed in -granules as well as on the cytoplasmic membrane of...
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Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units
Svatoňová, Jana ; Adam, Pavel (advisor) ; Matěj, Radoslav (referee) ; Zvěřina, Eduard (referee)
MUDr. Jana Svatoňová Autoreport for Dissertation Work Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units 1 Charles University in Prague 1st Faculty of Medicine Autoreport for Dissertation Work BIOLOGICAL BEHAVIOUR OF BETA2-MICROGLOBULIN IN LIQUOR IN CLINICALLY DEFINED NOSOLOGICAL UNITS MUDr. Jana Svatoňová 2014 MUDr. Jana Svatoňová Autoreport for Dissertation Work Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units 2 Contents Contents ............................................................................................... 2 1. Introduction .................................................................................. 3 2. Objective of this work .................................................................... 8 3. Material and methodology .............................................................. 9 4. Results .........................................................................................10 5. Discussion....................................................................................11 6. Conclusion ...................................................................................12 7. Literature: ....................................................................................12 8. The...
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Role of proteinase-activated receptor 2 in pathogeneiss of neurodegenerative diseases
Rohan, Zdeněk ; Matěj, Radoslav (advisor) ; Hermanová, Markéta (referee) ; Dundr, Pavel (referee)
This Thesis discusses the complex topic of the role of proteinase-activated receptors (PARs) in the physiology and pathophysiology of central nervous system diseases, and to some extent, the role of PARs in cancer pathobiology. Based on the results from this Thesis, we can conclude that PAR2 levels in the CSF do not track neuronal damage; therefore, PAR2 cannot be used as a marker of neuronal damage. Expression and activity of PAR2 in the brain appears to be mostly related to the activity of the disease process itself. To study the role of PAR2 in neurodegenerative diseases characterized by white matter and oligodendrocyte degeneration, a precise morphological descritption of individual diseases is essential. In the study aimed pathology of motor neuron disease we found reactive incre- ase in oligodendrocyte density in corticospinal tracts in reaction to white matter damage. In other study we confirmed the existence of a new variant of multiple system atrophy, atypical MSA (aMSA) charcterized by specific degenration of hippocampal neurons. Since the activity of kallikrein 6-PAR2 axis attenuates α-synuclein aggregation, its deficiency in hippocampus may be a prerequisite for its dominant degeneration leading to the develop- mant of α-synuclein neuronal inclusions and aMSA phenotype. Regarding the...
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Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units
Svatoňová, Jana ; Adam, Pavel (advisor) ; Matěj, Radoslav (referee) ; Zvěřina, Eduard (referee)
MUDr. Jana Svatoňová Autoreport for Dissertation Work Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units 1 Charles University in Prague 1st Faculty of Medicine Autoreport for Dissertation Work BIOLOGICAL BEHAVIOUR OF BETA2-MICROGLOBULIN IN LIQUOR IN CLINICALLY DEFINED NOSOLOGICAL UNITS MUDr. Jana Svatoňová 2014 MUDr. Jana Svatoňová Autoreport for Dissertation Work Biological behaviour of beta2-microglobulin in liquor in clinically defined nosological units 2 Contents Contents ............................................................................................... 2 1. Introduction .................................................................................. 3 2. Objective of this work .................................................................... 8 3. Material and methodology .............................................................. 9 4. Results .........................................................................................10 5. Discussion....................................................................................11 6. Conclusion ...................................................................................12 7. Literature: ....................................................................................12 8. The...
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