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Role of interaction between circadian and immune system in development of obesity and type 2 diabetes mellitus
Honzlová, Petra ; Sumová, Alena (advisor) ; Okuliarová, Monika (referee) ; Vodička, Martin (referee)
Disruptions within the circadian, metabolic, and immune systems contribute to the onset of metabolic illnesses, including type 2 diabetes. This doctoral thesis aimed to examine the mutual interactions between these three systems in relation to the development of metabolic disorders. The circadian system regulates a variety of mammalian physiological processes. On the molecular level, the circadian clock is in individual cells maintained by a complex of interconnected transcription-translation feedback loops. The circadian system is hierarchically organized, consisting of the central circadian clock residing within the suprachiasmatic nuclei (SCN) and of peripheral oscillators found in various organs and tissues, including the pancreas and compartments of the innate immune system such as macrophages and microglia. The central circadian clock synchronizes the peripheral oscillators via multiple pathways, including feeding- related metabolic changes to which some of the peripheral oscillators are highly sensitive. Misaligned feeding can thus induce dyssynchrony between individual peripheral oscillators. Our results show that a reverse restricted feeding (rRF) regimen, when food is available only for a limited time during the resting period of the day, has distinct effects on the circadian clocks in...
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Circadian regulation of the glymphatic system and its connection with the development of neurodegenerative diseases
Kuznetsov, Egor ; Sumová, Alena (advisor) ; Kubištová, Aneta (referee)
Due to the absence of an active lymphatic system of the brain and the responsible nodal system, it has long been unclear how interstitial metabolic waste products, in particular amyloid-β, tau- protein, α-synuclein and other biomarkers associated with the development of neurodegenerative diseases, are eliminated. A key role in this process is played by the glymphatic system, a complex network of tunnel-shaped perivascular spaces (PVSs) that conduct the flow of cerebrospinal fluid. These spaces are surrounded by astrocytes, responsible for the transport of fluids and the removal of metabolites. Studies suggest that the glymphatic system is subject to an endogenous circadian clock, and there is an established correlation between the volume of perivascular spaces and, with it, the rate of cerebrospinal fluid flow and sleep. Factors affecting the function of the glymphatic system include pulsation of blood vessels, spatial orientation of the body and functionality of aquaporin-4 (AQP4). Dysfunction of the glymphatic system plays a key role in the aging of the brain and the development of various neurodegenerative diseases. The aim of the work is to summarize the known knowledge about the regulation of the glymphatic system and its influence on the development and prevention of neurodegenerative...
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Chronotherapy as a new trend in the treatment of hypertension
Pafková, Patrícia ; Sumová, Alena (advisor) ; Alánová, Petra (referee)
Hypertension is still the leading cause of death and cardiovascular morbidity worldwide, but its long-term control remains unsatisfactory. Blood pressure is subject to certain variability during 24 hours, when its values are 10-20% lower at night than during the day. Due to the new knowledge that the circadian rhythm exists in almost all organ systems, interest in chronotherapy as a new trend in treatment is growing. This bachelor's thesis points out the importance of respecting circadian rhythms and includes current knowledge about chronotherapy of hypertension, together with an analysis of its benefits in the treatment of high blood pressure. Keywords: hypertension, circadian rhytm, antihypertensives, chronotherapy, blood pressure
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Role of glucocorticoids in synchronization of fetal suprachiasmatic nuclei
Janáčová, Klára ; Sumová, Alena (advisor) ; Lužná, Vendula (referee)
The development and entrainment of fetal suprachiasmatic nuclei (SCN) are controlled by maternal cues, including hormones that cross through the placenta in a circadian rhythm. A recent study highlighted the effect of glucocorticoids (GC) on fetal SCN both in vitro and in vivo, where the application of the synthetic glucocorticoid, dexamethasone (DEX) in vivo regulated the c-Fos gene expression (Čečmanová et al., 2019). Using organotypic SCN explants from embryonic day 17 (E17) of a transgenic mPer2Luc mouse model, this research built on the initial study to further elucidate the action of GC upon in vitro application. Real-time recording of PER2-bioluminescence in E17 SCN explants confirmed that DEX increases the amplitude of E17 SCN explants, and DEX application at CT 15-18 leads to a phase advance of the rhythm. The specificity of the DEX effect was confirmed by application of the glucocorticoid receptor antagonist, mifepristone. Inhibition of the protein kinase A and C signalling pathways, which regulate c-Fos gene expression had no effect on DEX action in vitro in E17 SCN explants. No effect of DEX on PER2 protein turnover was observed. Using a newly optimized RNA isolation method followed by RT-qPCR, an increased level of c-Fos was detected in E17 SCN explants 1h after DEX application at CT...
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Early ontogeny of the cell's circadian clock
Knapová, Adéla ; Sumová, Alena (advisor) ; Vácha, Martin (referee)
This thesis focuses on the development and function of the circadian system, which regulates biological processes in the body according to the 24-hour cycle. The circadian system and its key components, including the suprachiasmatic nuclei of the hypothalamus and peripheral oscillators, are introduced. The molecular operation of the circadian clock, which is influenced by two loops, is also discussed. A major theme is the ontogeny of the circadian clock, which occurs autonomously during embryonic stem cell differentiation. This process is influenced by various factors such as ultradian rhythms of the segmentation clock and the influence of maternal factors. However, not all signals are essential for the development of these clocks, and especially their rhythms, as revealed by in vitro methods. Furthermore, the thesis discusses how the behaviour of embryonic stem cells differs from cells differentiated from them, and why the circadian clock is dysfunctional in these cells. The work provides a deeper understanding of the ontogeny of the circadian system, its rhythms, and its regulatory mechanisms - that is, when, where and under what circumstances the clock starts to form and "tick".
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Synchronization of circadian clock in hippocampus
Kubátová, Eliška ; Sumová, Alena (advisor) ; Liška, Karolína (referee)
Circadian rhythms refer to the physiological, biochemical and behavioral changes of the organism with a period of about 24 hours, such as the cycle of sleep and wakefulness, the release of hormones, enzymatic activity or gene expression. Apart from the central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, we find many other peripheral oscillators in which we observe the rhythmic expression of clock genes. In this study, we focused on one of the peripheral brain oscillators located in the hippocampus. The hippocampus is best known for its role in memory formation through the mechanism of long- term potentiation (LTP). The formation of LTP is another process that exhibits circadian variation. Although the rhythmic expression of genes in the hippocampus has already been demonstrated, the mechanisms of synchronization of these clocks remain a subject of investigation. In this study, we studied the effect of candidate substances - N-methyl-D- aspartate (NMDA) and leptin on the circadian clock of the hippocampus. Genetically modified mPer2Luc mice were used as a model. The main goal of the work was to introduce a method of preparing organotypic explants of the hippocampus of these mice for monitoring the circadian clock in real time using the LumiCycle device. Next goal was...
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Circadian regulation of digestive system function and its disturbances due to external factors
Běloušková, Klára ; Sumová, Alena (advisor) ; Balounová, Kateřina (referee)
Circadian clocks regulate the behavior of cells in living organisms in 24hour periods. They react to environmental influences and, by synchronizing with them, ensure optimal cell function and the overall health of the organism. Biological clocks in the gastrointestinal tract and their functions can be influenced by several factors, including the timing of food intake or the influence of the microbiome. The correct timing of food intake can be essential in maintaining the functional physiology of the organism as well as the appropriate composition of the gut microbiome. Disruption of the synchronization between these factors and the biological clock in the gastrointestinal tract leads to disharmony of the organism, its improper function and the development of disease. The timing of food intake and the cultivation of an appropriate microbiome is critical to maintaining optimal health and should not be neglected by the public.
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Rhythmic function of placenta and the impact of disruption in maternal-placental-fetal axis
Světlíková, Nela ; Sumová, Alena (advisor) ; Pačesová, Dominika (referee)
In mammals, the circadian rhythms result of a complex endogenous system consisting of hierarchically organized oscillators. The system enables the synchronization of the organism's internal processes with the external environment. It consists of the main component, the central clock, located in the suprachiasmatic nuclei in the hypothalamus, and peripheral clocks in other cells, tissues and organs. The placenta is a temporary, specialized mammalian organ that is part of the mother-placenta-fetus axis and exhibits rhythmicity in its functions. The aim of this thesis is to summarize the rhythmic functions of the placenta, such as immunity, protection, and production of hormones and other mediators that play an important role in fetal development and pregnancy. In addition, the thesis also describes rhythmic changes, that occur during pregnancy in the mother-placenta-fetus axis and how these rhythms influence each other. Keywords Placenta, circadian clock, ontogenesis, fetus, maternal synchronization, hormones, enzymes, immunity
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Effect of maternal obesity on postnatal development of circadian clocks
Sejrková, Veronika ; Sumová, Alena (advisor) ; Spišská, Veronika (referee)
This thesis focuses on the synchronizing effect of obesity in mothers on ontogenesis of the circadian system in their offspring during gestation and postnatal life. Additionally, the work summarizes its impact on health of offspring in adulthood. During postnatal life, the central clock oscillator (SCN) is synchronized with external conditions through alternating period of light and darkness, but during prenatal ontogenesis of the main oscillator and peripheral oscillators, the SCN is synchronized with maternal signals, both behavioral, metabolic and hormonal. In the event of disruption of the maternal circadian and metabolic systems due to obesity, the circadian clocks of the offspring are incorrectly synchronized during gestation and breastfeeding, which may have a long-term effect on their health later during postnatal life. Maternal obesity is considered the main trigger for obesity occurring later.
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The role of posttranslational modifications in the molecular mechanism of the circadian clock
Janáčová, Klára ; Sumová, Alena (advisor) ; Sládek, Martin (referee)
The timing of the biological processes of organism is controlled by an endogenous circadian clock. The molecular clock is present in almost every cell and is synchronized with the external environment. The main mechanism of the clock is a transcription-translation feedback loop. The 24-hour circadian rhythm period is provided by reversible posttranslational modifications (PTMs) of the clock proteins and another regulators of the circadian clock. PTMs are further important for clock entrainment, their regulation by metabolic state in the cell, and reciprocal regulation of the circadian clock end cell cycle. Phosphorylation, histones PTMs, acetylation, SUMOylation, ubiquitination, O-linked N-acetylglucosamination and polyADP-ribosylation play a crucial role. The molecular mechanism of the biological clock is an evolutionarily conserved mechanism found in most organisms. This bachelor thesis summarizes the knowledge about the role of PTMs in the molecular mechanism of the mammalian and human circadian clocks. Key words: circadian clock, clock genes, clock proteins, posttranslational modifications
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