magistrsko delo
Gašper Fašun (Author), Aleš Fajmut (Mentor)

Abstract

Dušikov oksid (NO) je pomembna signalizacijska molekula v našem telesu. Posebno pomembno vlogo ima pri zagotavljanju ustreznega tonusa žil. Produkcija NO v žilah poteka v endotelni plasti, njegovo ciljno mesto delovanja pa so vaskularne gladke mišične celice (GMC), kjer sproža relaksacijo. Za odkritje vloge NO v našem telesu je bila podeljena Nobelova nagrada za medicino oziroma fiziologijo leta 1998. V uvodu tega dela predstavimo nekaj najpomembnejših študij in znanstvenikov na tem področju. Naštejemo tudi nekaj lastnosti ter funkcij NO in izpostavimo njegovo vlogo pri zdravljenju kardiovaskularnih bolezni. V nadaljevanju opišemo matematični model signalne poti NO v endoteliju, ki opisuje sklopitev strižne napetosti in produkcije NO v endotelnih celicah (EC). Strižno napetost zaznajo mehanosenzorji, ki aktivirajo encim endotelijsko sintazo NO (eNOS), ki producira NO. Mehanosenzorji, ki so upoštevani v matematičnem modelu, so ionski kanali, receptorji, povezani z G-proteini in integrini. Opisani model združimo z modelom, v katerem simuliramo učinkovanje NO v GMC. Glavnino magistrskega dela predstavlja prav nadgradnja in sklopitev teh dveh modelov preko prenosa NO iz endotelijskih v gladke mišične celice. Sklopitev je izvedena z enačbo, v kateri je opisana hitrost prehajanja NO v gladke mišične celice in tamkajšnje eliminacije. V GMC NO sproži produkcijo signalne molekule ciklični gvanozin monofosfat (cGMP) preko aktivacije encima topne gvanilat ciklaze (sGC). Hitrost produkcije cGMP v GMC opišemo s Hillovo funkcijo, ki temelji na odvisnostih, določenih v eksperimentih in predhodnih kinetičnih modelih. cGMP nato ključno vpliva na signalizacijo kalcija v GMC, od česar je odvisno tudi stanje relaksacije/kontrakcije GMC. Celosten model, ki je ustvarjen s sklopitvijo dveh parcialnih modelov, tj. modela signalne poti NO v EC in modela za od NO odvisne signalizacije Ca2+ in posledične relaksacije/kontrakcije GMC, nato verificiramo po delih. Posamezne rezultate celostnega modela primerjamo z rezultati parcialnih modelov, po katerih smo povzeli določene dele našega celostnega modela, ali pa so nam služili kot referenca pri njegovi izgradnji. Na podlagi primerjav identificiramo ključni parameter, s katerim je moč ustrezno kalibrirati celostni model. Ta parameter je hitrostna konstanta eliminacije NO v GMC (kdno), ki ključno vpliva na koncentraciji NO in cGMP v GMC. Predlagamo velikostni red vrednosti te konstante, ki rezultira tipične fiziološke vrednosti koncentracij NO in cGMP v GMC. Predlagana vrednost te konstante omogoča veliko odzivnost sistema na velike spremembe koncentracij cGMP, tj. preko več velikostnih redov, hkrati pa majhno senzitivnost sistema. S celostnim modelom na koncu napovemo od strižne napetosti odvisen časovni razvoj sile pod vplivom fiziološke holinergične stimulacije.

Keywords

magistrska dela;strižna napetost;dušikov oksid;ciklični gvanozin monofosfat;endotelij;gladke mišične celice;arterije;signalna pot;matematični model;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UM FNM - Faculty of Natural Sciences and Mathematics
Publisher: [G. Fašun]
UDC: 577.32(043.2)
COBISS: 24421640 Link will open in a new window
Views: 994
Downloads: 109
Average score: 0 (0 votes)
Metadata: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Other data

Secondary language: English
Secondary title: Modelling of the nitric oxide signalling pathway from the shear stress to the development of force in the arterial smooth muscle cells
Secondary abstract: Nitric oxide (NO) is an important signalling molecule in our body. It plays a particularly important role in ensuring proper vascular tone. NO production in blood vessels takes place in endothelium, and its target sites are smooth muscle cells (SMC), in which it triggers relaxation. For the discovery of the importance of the role of NO in our body the Nobel Prize for Medicine and Physiology was awarded in 1998. In the introduction section of this work, some of the most important studies and scientists within this field are presented, and some of the properties and functions of NO are listed along with the emphasis of its role in the treatment of cardiovascular diseases. This is followed by the presentation of the mathematical model that describes NO signalling pathway in the endothelium, which couples the shear stress and the production of NO in endothelial cells (EC). There mechanosensors detect shear stress, which leads to the activation of the enzyme endothelial nitric oxide synthase (eNOS) that produces NO. Mechanosensors, which are included in the mathematical model, are ion channels, G-protein coupled receptors and integrins. Further, we couple the model of endothelial NO production with the one that simulates the effects of NO in SMC. The main part of the master's thesis is thus focused on the upgrading and coupling of these two models. The coupling is carried out with the equation that describes the rate of transport of NO from EC into SMC and its rate of elimination there. In SMC NO triggers the production of the signalling molecule cyclic guanosine monophosphate (cGMP) via activation of the enzyme soluble guanylate cyclase (sGC). The rate of cGMP production in SMC is modelled with the Hill function and is based on the previous kinetic models and experiments. cGMP affects Ca2+ signalling that determines consequent state of SMC contraction. An integral model, created by coupling of two main partial models, i.e. the NO signalling pathway model in the EC and the model for NO dependent relaxation of SMC, is then evaluated by parts. Hence, individual results of the integral model are compared with the results of the partial models that were used as building blocks or as a reference for the construction of the integral model. On the basis of these comparisons we identify a key parameter that enables efficient calibration of the integral model. This parameter is the rate of the NO elimination in SMC (kdno), which crucially affects the concentrations of NO and cGMP in SMC. We propose the order of magnitude of its value, which result in typical physiological levels of NO and cGMP in SMC. The proposed values of this parameter allow large responsiveness with respect to large changes in cGMP concentrations, i. e. over several orders of magnitude, and at the same time, small sensitivity of the system. Finally, the integral model enables prediction of the shear-stress-dependent time evolution of force under the physiological levels of cholinergic stimulation.
Secondary keywords: master theses;shear stress;nitric oxide;cyclic guanosine monophosphate;endothelium;smooth muscle cells;arteries;signalling pathway;mathematical model;
URN: URN:SI:UM:
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za naravoslovje in matematiko, Oddelek za fiziko
Pages: VII, 76. str.
ID: 11009623