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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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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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CIrcadian regulation of miRNA and clock-controlled genes in tumorigenesis
Balounová, Kateřina ; Pácha, Jiří (advisor) ; Bendová, Zdeňka (referee)
The circadian clock generates circadian rhythms, which participate on regulation of a number of signalling pathways. Disruption of the circadian regulatory mechanism is linked to a development and a progression of certain types of cancer including colorectal tumorigenesis. Progression of tumorigenesis depends on the cell cycle machinery related to cell proliferation and apoptosis. MiRNAs play a role in initiation and progression of tumorigenesis because they interfere in regulatory pathways associated with tumorigenesis. The aim of the thesis was to determinate existence of circadian rhytms in clock controlled genes (Tef, Dbp), miRNAs (miR-1-3p, miR-16-5p, miR-34a-5p, miR-155-5p, miR-192-3p) and genes of the cell cycle machinery (Ccnd1, Ccne1, Ccna1, Ccnb1) and apoptosis (Casp3, Bcl2, Bad). Further, to compare detected circadian rhythms during aging and neoplastic transformation of colon by quantitative RT-PCR. We have observed circadian expression of Tef, Dbp, Ccne1, Ccna1, Ccnb1, Casp3 and Bcl2 in young mice colon, Tef, Dbp, miR-1-3p, Ccne1, Ccna1 in old mice colon and Tef and Dbp in colorectal tumors. In summary, circadian expression of clock controlled genes varied but was maintained in mice colorectal tumors. In aging we demonstrated weakening of circadian rhythms of the genes of the cell...
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Circadian clocks in the brain and their function
Miklasová, Veronika ; Sumová, Alena (advisor) ; Kubová, Hana (referee)
In the brain, there is a center regulating circadian rhythms, which is located in the SCN. Outside these nuclei, there are other structures, which contribute significantly to coordination of circadian rhythms. Most of those nuclei are located in the hypothalamus and are connected with the SCN. These areas are involved in the management of basic physiological functions such as thermoregulation, food intake, sleep/wake cycles, hormonal secretion and control of locomotor activity. Outside the hypothalamus, there are other clocks, which work according to their location, e.g., clock in the limbic system participates in the control of cognitive functions. The olfactory lobe and retina harbor autonomous clocks that operate independently of the SCN. This work is focused on summary of the information about the selected extra- SCN oscillators in the brain their regulation of physiological functions. Key words: clock genes, circadian clocks, brain
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