magistrsko delo
Katarina Meštrović (Author), Aleš Fajmut (Mentor)

Abstract

V magistrski nalogi preučujemo molekularne mehanizme vpliva cikličnega gvanozin monofosfata (cGMP) na kalcijevo (Ca2+) signalizacijo v gladkih mišičnih celicah (GMC) arterij ter posledično na njihovo kontrakcijo oziroma relaksacijo. Obstoječi fizikalno-matematični model, ki vsebuje šest mehanizmov, preko katerih cGMP posredno ali neposredno vpliva na signal Ca2+, nadgradimo z dvema dodatnima mehanizmoma delovanja cGMP. To sta vpliv cGMP na od Ca2+ odvisne klorove (Cl-) kanale (ClCa), ki se nahajajo v celični membrani, in na črpalke za Ca2+ v membrani sarkoplazemskega retikuluma (SERCA). Študij vpliva cGMP na ClCa je zanimiv predvsem zaradi razlik med tipi teh kanalov v pljučni in mezenterični arteriji. Mezenterična arterija vsebuje dva tipa ClCa kanalov: od cGMP neodvisne ClCa in od cGMP odvisne ClCa (ClCacGMP), medtem ko pljučna arterija vsebuje zgolj od cGMP neodvisen tip teh kanalov (ClCa). S fizikalno-matematičnim modelom za oba tipa arterij simuliramo učinek cGMP na signal Ca2+ v GMC, ki se lahko izraža v obliki oscilacij ali stacionarnega stanja ter določimo povprečno koncentracijo Ca2+ v citoplazmi, ki odraža stopnjo kontrakcije. Poleg tega preučujemo tudi vpliv cGMP na SERCA. Rezultati simulacij kažejo, da visoka koncentracija cGMP v modelu, ki vključuje ClCacGMP, privede do povišane povprečne znotrajcelične koncentracije Ca2+. To se zgodi pri koncentracijah nad 10 µM. Nasprotno pa v modelu brez kanalov ClCacGMP višanje koncentracije cGMP zniža povprečno znotrajcelično koncentracijo Ca2+, kar je skladno s pričakovanji glede relaksacijskega učinka pri visokih koncentracijah cGMP. Iz simulacij je tudi razvidno, da je kanal ClCacGMP zaradi svoje večje občutljivosti na Ca2+ pri visokih koncentracijah cGMP odgovoren za povečan vstop Ca2+ v celico, kar povzroči višjo koncentracijo citosolnega Ca2+ v mezenterični arterij.

Keywords

magistrska dela;gladka mišična celica;ciklični gvanozin monofosfat;od kalcija odvisni klorovi kanali;pljučna arterija;mezenterična arterija;kalcijeva signalizacija;fizikalno-matematični model;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UM FNM - Faculty of Natural Sciences and Mathematics
Publisher: [K. Meštrović]
UDC: 577.32(043.2)
COBISS: 234881027 Link will open in a new window
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Other data

Secondary language: English
Secondary title: Comprehensive model of the impact of cyclic guanosine monophosphate on the molecular mechanisms of intracellular calcium signaling in arterial smooth muscle cells
Secondary abstract: In this work, we study the molecular mechanisms through which cyclic guanosine monophosphate (cGMP) affects calcium (Ca2+) signaling in arterial smooth muscle cells (SMC) and consequently their contraction and relaxation. An existing mathematical model, encompassing six mechanisms by which cGMP directly or indirectly modulates Ca2+ signaling, is upgraded with two additional mechanisms. These newly integrated mechanisms involve the effect of cGMP on calcium-dependent chloride (Cl-) channels (ClCa) located in the cell membrane and on the calcium pumps in the membrane of the sarcoplasmic reticulum (SERCA). The study of cGMP effect on ClCa is particularly interesting due to differences between these channel types in pulmonary and mesenteric arteries. The mesenteric artery contains two types of ClCa: cGMP-independent ClCa and cGMP-dependent ClCa channels (ClCacGMP), whereas the pulmonary artery contains solely the cGMP-independent type (ClCa). With the upgraded mathematical model, we simulate the effects of cGMP on Ca2+ signaling in SMCs of both artery types, which can exhibit oscillatory behavior or a constant Ca2+ concentration over time. The simulations determine the average intracellular Ca2+ concentration, reflecting the extent of cellular contraction. Additionally, we study the impact of cGMP on SERCA. Simulation results show that a high concentration of cGMP in the model which includes ClCacGMP result in elevated average intracellular Ca2+ concentration. This effect occurs at concentrations higher than 10 µM. In the model lacking ClCacGMP, an increase in cGMP reduces the average intracellular Ca2+ concentration, aligning with expected relaxation effects at high cGMP. Furthermore, simulations reveal that due to their higher sensitivity to Ca2+ at elevated cGMP concentrations, ClCacGMP are responsible for increased Ca2+ influx into the cells, resulting in higher intracellular Ca2+ concentration in the mesenteric artery.
Secondary keywords: master theses;smooth muscle cell;cyclic guanosine monophosphate;calcium-dependent chloride channels;pulmonary artery;mesenteric artery;calcium signaling;mathematical model;Univerzitetna in visokošolska dela;
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za naravoslovje in matematiko, Oddelek za fiziko
Pages: 45 f.
ID: 26218736