(magistrsko delo)
Manja Sluga (Author), Milan Brumen (Mentor), Aleš Fajmut (Co-mentor)

Abstract

V magistrskem delu najprej sistematično predstavimo poznane mehanizme zaznavanja strižne napetosti, njihov vpliv na endotelij karotide in drugih arterij ter vlogo poznanih mehanizmov na produkcijo dušikovega oksida (NO). Ključni mehanosenzorni kompleksi, ki se aktivirajo ob spremembah strižne napetosti in ki sprožajo različne signalne poti v endotelnih celicah, so ionski kanali, receptorji tirozin kinaze, G-proteini, kaveole, adhezijski proteini, citoskelet, glikokaliks in primarne migetalke. Večjo pozornost v nalogi posvetimo tudi opisom mehanosenzornega kompleksa medceličnih stikov, ki mu je v zadnjem času pripisana vedno večja vloga pri mehanotransdukciji strižne napetosti in aktivaciji anti-aterosklerotičnih signalnih poti. V nadaljevanju obravnavamo matematični model, ki kot mehanotransduktorje vključuje ionske kanale, integrine in receptorje, povezane z G-proteini. Model ovrednotimo z namenom ugotavljanja njegove zmožnosti za reprodukcijo relevantnih izmerjenih podatkov produkcije NO. Ugotovitve primerjamo še z drugim modelom, ki upošteva vpliv zgolj dveh mehanoreceptorjev (integrinov in receptorjev, povezanih z G-proteini), toda podrobneje opisuje vplive kompleksa kalcij/kalmodulin (Ca2+/CaM), encima protein kinaza B (Akt) ter stresnega proteina (Hsp90) na aktivnost encima endotelijska sintaza dušikovega oksida (eNOS). Za razliko od prvega modela drugi ne vključuje inhibitornih vplivov encima protein kinaza C (PKC) in nukleotida cikličnega gvanozin monofosfata (cGMP) na aktivnost eNOS in kodacijo signala Ca2+. Modela sta skladna v tem, da v obeh primerih strižna napetost v endotelijski celici sproži produkcijo inozitol trifosfata (IP3), kar vodi do sproščanja Ca2+ iz znotrajceličnih shramb in do kodacije podobnih signalov Ca2+. V obeh modelih je odziv produkcije NO na strižno napetost dvofazen, pri čemer je za pojav druge faze bistvenega pomena signalna pot, ki vključuje encima fosfoinozitid 3-kinazo (PI3K) in Akt. Oba encima imata ključno vlogo pri fosforilaciji encima eNOS, ki je potrebna za dosego njegove največje aktivnosti. Čeprav noben izmed modelov ni povsem popoln, pa vsak izmed njiju omogoča poglobljen in sistematičen vpogled v razumevanje kompleksnih biokemijskih procesov, ki jih lahko sproži strižna napetost v karotidi, in hkratno kvantitativno ovrednotenje pomembnosti posameznih signalnih poti in procesov.

Keywords

strižna napetost;endotelij;mehanotransdukcija;mehanosenzorni kompleks;dušikov oksid;matematični model;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UM FZV - Faculty of Health Sciences
Publisher: [M. Sluga]
UDC: 616.12(043.2)
COBISS: 2385828 Link will open in a new window
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Other data

Secondary language: English
Secondary title: Shear stress effects of blood flow on the carotid endothelium
Secondary abstract: In this master thesis systematic descriptions of known mechanisms of shear stress detection, their effect on the endothelium of the carotid and other arteries, as well as the role of known mechanisms on the production of nitric oxide (NO) are presented. The key mechanosensing complexes that respond to changes in shear stress and which trigger different signalling pathways in endothelial cells are: ion channels, tyrosine kinase receptors, G-protein coupled receptors (GPCR), kaveoles, adhesion proteins, cytoskeleton, glycocalyx and primary cilia. More attention was paid to the description of intercellular coupling, which has an increasing role in mechanotransduction of shear stress and activation of anti-atherosclerotic signalling pathways. Further, we present a mathematical model that includes ion channels, integrins and GPCR as mechanosensors. The model is evaluated in order to determine its ability to reproduce the relevant measured data on the NO production. That model is compared with another model that takes into account the influence of two mechanosensors (integrins and GPCR) but includes a more detailed description of the effects of calcium/calmodulin (Ca2+/CaM) complex, protein kinase B (Akt) and heat-shock protein (Hsp90) on the activity of the enzyme endothelial nitric oxide synthase (eNOS). The latter does not include the inhibitory effect of the enzyme protein kinase C (PKC) and the nucleotide cyclic guanosine monophosphate (cGMP) on the activity of eNOS and the encoding of Ca2+ signal. In both models shear stress triggers the production of inositol tris-phosphate (IP3), leading to the release of Ca2+ from intracellular stores and to the encoding of similar Ca2+ signals. In both models, the NO production profile is biphasic, whereby the signalling pathway involving the phosphoinositide 3-kinase (PI3K) and the enzyme Akt are essential for the occurrence of the second phase. It is found out that these two enzymes play a key role in the phosphorylation of the eNOS enzyme needed to achieve its maximal activity. Although none of the models is complete, they provide an in-depth and systematic insight into the understanding of complex biochemical processes that are triggered by shear stress in carotid artery. And, moreover, they both allow quantitative evaluation of the significance of individual signalling pathways and processes.
Secondary keywords: shear stress;endothelium;mechanotransduction;mechanosensory complex;nitric oxide;mathematical model;Shear Strength;Endothelium;Nitric oxide;Strižna napetost;Endotelij;Dušikov oksid;
URN: URN:SI:UM:
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za zdravstvene vede
Pages: VIII, 67 str.
ID: 10869185