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Role of intestinal circadian clock in epithelial transport, proliferation, and tumourigenesis
Soták, Matúš
AABBSSTTRRAACCTT The molecular circadian clock enables anticipation of environmental changes. In mammals, clocks are ubiquitously present in almost all tissues and they are comprised of transcriptional-translational feedback loops of the so-called clock genes. The central clock represents the intrinsic pacemaker which is located in suprachiasmatic nuclei (SCN) of hypothalamus and synchronizes peripheral clocks. Clockwork system in alimentary tract and its regulatory link to intestinal functions are poorly understood. Therefore the objective of the thesis was to characterize molecular clock in particular parts of the rat intestine and to elucidate its link to the intestinal transport, regulation of cell cycle and neoplastic transformation in colonic tissue. We used quantitative RT-PCR (qPCR) to determine circadian profiles of mRNA expression of clock genes in the epithelium of duodenum, jejunum, ileum, and colon of rat. Furthermore, we analysed the expression of genes coding sodium chloride transporters and channels as well as cell cycle regulators in colon. To focus more precisely on different structures of intestinal epithelia we used laser capture microdissection. In addition, we performed Ussing chamber measurements to determine the colonic electrogenic transport. To study the contribution of circadian...
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Molecular mechanism of circadian clock and its connection to neuropsychiatric disorders
Jandová, Eliška ; Sumová, Alena (advisor) ; Mašek, Tomáš (referee)
Circadian rhythms, which are running with a period of 24 hours, are in mammals controlled via principal clock located in the area of suprachiasmatic nuclei (SCN) and peripheral oscillators. The basic molecular mechanism governing the circadian rhythms is the transcriptional-translational feedback loop of clock genes Clock, Bmal1, Per and Cry. The CLOCK-BMAL1 protein dimer acts as an activator for the transcription of the Per and Cry genes, which retroactively inhibit this dimer and thus its own transcription. This main loop affects other genes that are involved in regulation of the core loop. The function, nuclear localization and stability of clock genes are affected by a number of postranscriptional and postranslational modifications. Sleep disorders, one of the main processes controlled by the clock genes, accompany many neuropsychiatric disorders, including autism spectrum disorder. The development of these disorders have been associated with the clock genes or their interactions with other genes that play a major role in development of these disorders.
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The effect of constant light in early development on the circadian system in the adulthood
Kubištová, Aneta ; Bendová, Zdeňka (advisor) ; Jelínková, Dana (referee)
Long-term exposure to constant light results in desynchronization of the circadian system in an adult and is associated with reduced efficiency of many physiological functions timed to the exact time of day, or with the development of some of the so-called civilization diseases. Constant light in adults also results in deterioration of the cognitive abilities or changes in the sleep structure. The effect of night light on the health of an adult organism is studied mainly in connection with shift work or with light pollution. The question of what effect the increased level of night light has on the development of the organism, especially on the development of the nervous system and the circadian system itself, is less studied. This diploma thesis focused on the identification of the extent of changes in the expression of Per2, Nr1d1, Stat3, BDNF genes, as well as genes encoding NMDA receptor subunits and some tissue-specific genes in the retina. Our experiments were performed on adult Long-Evans rats, that spent the first 20 days of their postnatal development in low-intensity constant light. Changes in expression were determined by quantification of mRNA by RT-qPCR in the structures of the frontal and parietal cortex, olfactory bulb, hippocampus, suprachiasmatic nucleus and retina. Behavioral tests...
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The role of Wnt signaling in interaction between circadian clock and cell cycle
Herrmannová, Terezie ; Sumová, Alena (advisor) ; Macůrková, Marie (referee)
The Wnt signaling represents a highly conserved signal transduction cascade that regulates stem cell proliferation and differentiation. It plays an irreplaceable role not only during embryonic development, but also in maintaining homeostasis of adult tissues. The cell division is also influenced by the circadian clock. The clock can interact with the cell cycle either directly within a single cell or regulate it intercellularly. In order to impact surrounding cells, it uses the Wnt signaling pathway that mediates signal transduction through the extracellular space. Both Wnt signaling and the circadian clock are essential for the physiological functioning of the mammalian organism, and their disruption can lead to the development of cancer. Keywords: circadian clock, clock genes, cell cycle, Wnt signaling, cell proliferation, cancer
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Molecular mechanisms of mammalian circadian clocks, its sensitivity to constant light and aging
Novosadová, Zuzana ; Sumová, Alena (advisor) ; Doležel, David (referee) ; Mráz, Miloš (referee)
Many processes in mammalian body exhibit circadian rhythms. These rhythms are driven by an intricate system composed of the central pacemaker, suprachiasmatic nuclei (SCN) in the brain, which entrains the peripheral oscillators in various organs, such as pancreas, liver, colon and lungs. Circadian clocks are autonomously driven in each cell based on molecular circuits involving so called clock genes, such as BMAL, CLOCK, PER and CRY. Age- dependent impairment of physiological functions of mammalian body, such as behaviour and metabolic functions, has been well documented. However, it has not been fully elucidated whether the impairment is linked with worsening of the circadian clock function. The aim of our study was to find out whether i) aging affects basic properties of the circadian clock in SCN and peripheral organs, such as pancreas, colon, liver and lungs, ii) aging- induced changes in glucose homeostasis affect the properties of the circadian clock in the pancreas, and iii) the sensitivity of circadian clock in SCN and peripheral organs to disturbances in environmental lightning conditions is altered during aging. We used groups of adult (9 months) and aged (25 months) animals which were subjected to 3 different light regimes, namely to light/dark regime (LD 12:12), constant light (LL) and...
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Impact of circadian system disruption on development of gastrointestinal disorders
Kubištová, Aneta ; Sumová, Alena (advisor) ; Červená, Kateřina (referee)
The ability to sense 24-hour cycles in external environment and to adapt to them is present in a great array of species living on the Earth. Mammals possess internal time-keeping system which is composed of circadian clocks located in the suprachiasmatic nuclei (SCN) of the hypotalamus and peripheral clocks in various tissues and organs of the body. These clocks are adapting to the changes of external environment, such as light and dark cycles or feeding cycles. Peripheral clocks in the organs of the digestive system are synchronized with the signals derived from the central clock in the SCN and also with signals from food intake. Discordance between these signals may result in development of various diseases of the gastrointestinal tract (GIT) related to insufficient digestion or even in higher risk of developing a cancer. This bachelor thesis is generally aimed at circadian rhythms in the body, with the focus on rhythms in the GIT. It will deal with the importance of the circadian rhythms for correct GIT functions. Furthermore, the thesis is focused on connection between the desynchonization of the circadian clock and GIT disease development, namely of obesity and cancer.
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Mechanisms of maternal entrainment of the fetal circadian clock
Černá, Barbora ; Sumová, Alena (advisor) ; Balaštík, Martin (referee)
Our body is influenced by many cyclical changes in the environment, such as day and night or seasons. To predict these changes and react to them in time, the organism is equipped with inner clock, which rhythmically influences many physiological processes, such as sleep or metabolic rhythms. Disrupting our inner rhythms at molecular and behavioral levels contributes to many serious disorders. It is necessary that all mechanisms of the inner circadian clock are developed and set up properly. Circadian clocks are set up by the mother, who passes rhythmical information about day and night cycle on to her embryo. Though a great attention is devoted to revealing the nature of this synchronization between the mother and her pup, the mechanisms of this process have not been fully understood yet. The aim of this thesis is to contribute to actual understanding of this synchronization. Experiments, performed in this thesis, relate to studying the ability of maternal signals to synchronize embryos with the environment. Feeding and light regime of pregnant rats was manipulated and the effect of these changes on the neuronal activity within the suprachiasmatic nuclei of 19-day embryos was analyzed.
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Molecular mechanisms of circadian clock entrainment by daily regime in food intake
Kapoun, Jiří ; Sumová, Alena (advisor) ; Červená, Kateřina (referee)
Circadian clocks form an endogenous time-keeping system present in most organisms, synchronizing physiological and behavioural processes with perodically changing environmental conditions. The system comprises of the master clock in the suprachiasmatic nuclei of the hypothalamus and numerous subsidiary clocks in peripheral tissues. Its molecular design is constituted by the clock genes, which are rhythmically expressed, form a series of transcriptional/translational feedback loops and influence the expression of various other genes involved in metabolic pathways. The peripheral clocks are dependent on the master clock, although they can be entrained with external cues like food intake timing and diet composition. This desynchronization leads to the distruption of clock gene oscillation, which can potentially have serious impact on metabolic processes and increase the risk of metabolic disorders. The aim of this thesis is to summarize current knowledge on the relationship of molecular chronobiology and nutrition with a focus on the molecular mechanisms through which can food, especially its intake timing and composition, influence the crosstalk between clock gene expression and cellular metabolism. The thesis also emphasises the potential effect of circadian clock disruption on the risk of metabolic...
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