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Analýza vybraných genových polymorfismů a její význam pro individualizovanou farmakoterapii
ŘEŽÁBKOVÁ, Kristina
This thesis deals with the metabolism of xenobiotics and the fact that it may be influenced by genetic polymorphisms in pharmacogens. In the experimental part, samples of volunteers and patients were tested by several methods of molecular biology detecting these polymorphisms and the results were interpreted and compared on the basis of available studies. Furthermore, the work highlights methods that would lead to successful individualized pharmacotherapy in similar clinical trials.
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Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
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Analysis of gene polymorphism of CYP 2C19 patients treated with clopidogrel
MAŠKOVÁ, Soňa
Clopidogrel is an antithrombotic medicament from the group of thienopyrids, used for the prevention of blood cloths by the patients with acute coronary syndrome, patients after an ischemic stroke, myocardial infarction or by the patients with proven lower limb ischemia. Clopidogrel is a "prodrug", which means that it needs to be metabolised into an active metabolite before it stars working. The cytochrome P450 2C19 plays the main role in the bioactivation of clopidogrel. Individual enzymes of cytochrome complex are coded by genes, which are polymorphic. The function of P450 2C19 can differ by individuals, from the reason of gene polymorphism, therefore the bioactivation of clopidogrel can differ as well. There are few alleles of cytochrome P450 CYP2C19, which are connected with different therapeutic reactions on the submission of clopidogrel. Individuals with the allele CYP2C19*17 have an increased concentration of active metabolite and are at a higher risk of bleeding complications. The carriers of CYP2C19*2 a CYP2C19*3 alleles have a decreased metabolisation of clopidogrel into an active metabolite, which leads to insufficient antiaggregate effect and to increased appearance of cardiovascular complications. The allele CYP2C19*1 is connected with a fully functioning metabolism. In the group of 512 patients, we detected 191 carriers of the genotype *1/*1, 79 carriers of the genotype *2/*1, 12 carriers of the genotype *2/*2, 1 carrier of the genotype *3/*1, 43 carriers of the genotype *17/*17, 146 carriers of the genotype *17/*1 and 40 carriers of the genotype *17/*2. The stratification of the patients according to genotype CYP2C19 has a significant meaning for adjusting the right treatment strategy and it is a prevention of stroke and the risk of bleeding.
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Structural biology of the enzymes involved in mercaptopurine metabolism
Soldánová, Anna ; Maloy Řezáčová, Pavlína (advisor) ; Novotný, Marian (referee)
Mercaptopurine (6-mercaptopurine) together with azathioprine and 6-thioguanine belong to a group of widely used chemotherapeutics and immunosuppressants. However, insufficient therapy outcome or severe adverse effects such as myelosuppression are still being reported. Technological progress in DNA and RNA sequencing facilitates effective identification of causative genes responsible for the therapy failure, i.e., description of genetic variants for enzymes involved in metabolism of physiological purines as well as thiopurine drugs. Variants of these enzymes may substantially alter concentrations of cytotoxic forms of thiopurines, which affect therapy success rates. Currently, a number of mutations in genes that play role in thiopurine metabolism have been annotated. Nevertheless, molecular mechanisms underlying the effect of these mutations are not fully elucidated. Knowledge of 3D structure for these enzymes may shed light on the effect of the genetic variants to protein function and mechanisms modulating therapeutic efficacy of thiopurines. This thesis focuses mainly on biochemical and structural characterization of thiopurine-S-methyltransferase, fosfatase NUDT15 and cytosolic 5′-nucleotidase II. It summarizes current state of knowledge and emphasizes the importance of structural biology methods for...
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Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
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