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A role of Sirt1 in the Notch signalling pathway.
HORVÁTH, Matej
The aim of this thesis was to examine role of Sirt1 in the Notch signalling pathway, using Drosophila as a model organism. Based on in vivo and in vitro studies, we conclude that Sirt1 plays a positive role in Notch signalling. In embryonic S2N cells, Sirt1 is responsible for the protection from metabolic stress-induced down-regulation of subset of E(Spl) genes. During development, Sirt1 is responsible for proper Notch-dependent specification of SOPs and wing development. Sirt1 can regulate the Notch signalling on multiple levels via deacetylation of various substrates involved in the Notch signalling revealed by our proteomic survey.
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The impact of SIRT1 inhibition on zebrafish morphology and behavior
Faustová, Zuzana ; Červený, Lukáš (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Zuzana Faustová Supervisor: Prof. Doutor Jorge Miguel de Ascenção Oliveira PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: The impact of SIRT1 inhibition on zebrafish morphology and behavior After discovery of connection between yeast Silent Information Regulator 2 (Sir2) and its ability to alter lifespan, Sir2 and its seven mammalian orthologs became very attractive therapeutic target. These so called sirtuins are members of a histone deacetylase family. They possess unique catalytic activity having nicotinamide adenine dinucleotide as a cofactor and their function can be influenced by environmental factors. The aim of this diploma thesis was to extend knowledge of Sirtuin 1 (SIRT1), which is from all mammalian sirtuins considered to have the closest relation to yeast Sir2. At first we tested the impact of SIRT1 inhibition on early developmental stages of zebrafish (Danio rerio) embryos and larvae, finding out that SIRT1 is important for normal development and SIRT1 inhibition or malfunction result in cardiovascular defects, delayed development, and death. Additionally, we tried to learn more about SIRT1 and its connection with Parkinson's disease by combining nontoxic doses...
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Relation between n-3 polyunsaturated fatty acids and cellular sensors of energetic state
Zouhar, Petr ; Pecina, Petr (referee) ; Flachs, Pavel (advisor)
The important factor in regulation of metabolic processes is regulatory proteins, which are able to react by feed-back to energetic state of the cell. Big attention is focused on the AMP activated kinase (AMPK) and NAD+ activated deacetylase SIRT1. These enzymes interact together and their stimulation increases mitochondrial biogenesis and fatty acid oxidation. Due to this it functions beneficially against the onset of obesity, insulin resistance and ageing. Fasting, exercise and some antidiabetogenic drugs act by these regulators. n-3 polyunsaturated fatty acids (PUFA) are also known because of their stimulative effects on mitochondrial biogenesis and -oxidation. Previous work of our group have showed that intake of higher dose of n-3 polyunsaturated fatty acids (PUFA) in diet lead to increase in activity of AMPK in white adipose tissue. New results presented in this thesis show that SIRT1 is essential for increase in expression of stimulators of -oxidation (PPAR etc) in response to n-3 PUFA in diet. n-3 PUFA futher improve the metabolic profile synergistically with calorie restriction probably through SIRT1.
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The Interplay Between the Notch Signaling Pathway and Cellular Metabolism
SLANINOVÁ, Věra
We identified four metabolic genes as direct targets of Notch signaling pathway both in vitro and in vivo and investigated the hypothesis that Notch directed metabolic changes support the growth of the imaginal wing dics. Vice versa, we observed the influence of metabolic changes on the activity of Notch signaling pathway and we identified Sirt1 as a metabolic sensor for the Notch pathway that helps to elicit an efficient response to Notch signal, in a metabolism sensitive manner.
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Role of sirtuins in pronucleus formation in vitro fertilised porcine oocytes
Maryníková, Veronika ; Žalmanová, Tereza (advisor) ; Miriama , Miriama (referee)
Recently, the increasing importance of reproductive biotechnologies rises. They provide us to get higher performance of livestock or to improve treatment in human medicine. It is neccessary to have a sufficient amount of developmentaly competent oocytes and further healthy liveable embryos for in vitro culture to supply a progress of reproductive technologies. Immediately after fertilization, pronucleus formation is a key moment for
further embryonicdevelopment. Male and female pronuclei have their own pattern of histone code. For development of early embryo, it is neccessary to supply the correct pattern of histone code. NAD+-dependent histon deacetylases, sirtuins, are one of the mechanism which
plays in regulation of histone code. These family contains seven isoforms, SIRT1-7.
Based on current research, we decided for hypothesis that sirtuins are present in porcine fertilized oocytes and regulate the pronucleus formation. In this thesis, porcine COCs were culture in modificated culture medium and after 44 hr. maturation, only oocytes with extruded first polar body were chosen and used for further in vitro fertilization. Presumed zygotes were subsequently cultured with sirtuins inhibitors, nicotinamide or sirtinol. After 22 hr. of in vitro culture, zygotes were subjected by imunocytochemicaly localization of
methylated and acetylated (on lysine K9) histone H3 and image analysis.
Our results show that SIRT1 is localizated in porcine zygotes, especially in pronuclei. There are changes in acetylation and methylation H3K9 after sirtuin inhibition. Significant increase of H3K9 acetylation and decrese in H3K9 methylation are appeared. Sirtinol usage
has confirmed that the changes are result of SIRT1 action. Role of SIRT1 in histone code regulation of pronucleus formation is still not enought described in porcine.
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