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Title:MODEL REGULACIJE ENCIMA FOSFATAZE LAHKIH VERIG MIOZINA V RAZVOJU SILE V GLADKIH MIŠICAH
Authors:ID Založnik, Vanja (Author)
ID Fajmut, Aleš (Mentor) More about this mentor... New window
Files:.pdf MAG_Zaloznik_Vanja_2015.pdf (2,00 MB)
MD5: 6C7BB6DC6BE33434664C6A68B87AE361
 
Language:Slovenian
Work type:Master's thesis/paper
Typology:2.09 - Master's Thesis
Organization:FZV - Faculty of Health Sciences
Abstract:V magistrski nalogi preučujemo ključne mehanizme za razvoj sile v gladkih mišičnih celicah (GMC). Razvoj sile pri holingerični stimulaciji gladkih mišic poteka v dveh fazah. V prvi fazi v časovnem intervalu ene minute sila naraste na 80‒90 % maksimalne vrednosti sile. V drugi fazi se v časovnem intervalu tridestih minut sila razvije za nadaljnih 10‒20 % maksimalne vrednosti sile. V nalogi se ostredotočimo predvsem na to drugo ‒ počasnejšo fazo razvoja sile v gladkih mišičnih celicah. Na podlagi vedenj o encimu fosfatazi lahkih verig miozina (MLCP) in o njegovi vlogi v procesu krčenja gladkih mišic dihalnih poti nadgradimo obstoječi model za simulacijo časovnega razvoja sile v odvisnosti od signala kalcija. Model nadgradimo tako, da v njem eksplicitno modeliramo vpliv Rho kinaze (ROCK) na inhibicijo katalitične podenote (PP1c) encima MLCP preko fosforilacije proteina CPI-17. V model prav tako vključimo časovni potek fosforilacije dveh treoninskih ostankov (T696 in T853) na regulatorni podenoti (MYPT1) encima MLCP, ki temelji na izmerjeni odvisnosti. V modelu predpostavimo, da vsi trije omenjeni elementi, CPI-17, T696 in T853, inhibirajo katalitično enoto PP1c. Inhibitorni učinek modeliramo z reverzibilno kompetitivno inhibicijo. Model temelji na predpostavki, da vsa tri mesta fosforilacije: eno na fosforiliranem proteinu CPI-17 in skupaj dve na mestih fosforilacije T696 in T853 na regulatorni podenoti MYPT1, interagirajo s katalitično podenoto PP1c istega encima MLCP, in na ta način zmanjšajo njegovo aktivnost. Z modelom lahko razložimo dodatni porast sile v drugi fazi razvoja za dodatnih 10‒20 %. Z modelom simuliramo tudi učinek inhibitorja encima ROCK, kot če bi bil encim ROCK udeležen zgolj v procesu fosforilacije proteina CPI-17 in za primer, če bi bil encim ROCK udeležen tako v procesu fosforilacije proteina CPI-17, kot tudi v procesu fosforilacije treoninskih ostankov na MYPT1. Na podlagi modela se kot bolj verjeten izkaže drugi mehanizem. Z modelom ocenimo, da bi lahko bil prispevek ROCK k fosforilaciji T696 in T853 na dolgi časovni skali 70 %. Z modelom tako v celoti potrdimo zastavljene hipoteze, hkrati pa oblikujemo nove.
Keywords:gladka mišična celica, matematični model, inhibicija, razvoj sile, kalcij, encimska kinetika
Place of publishing:Maribor
Publisher:[V. Založnik]
Year of publishing:2015
PID:20.500.12556/DKUM-47158 New window
UDC:576.32/.36(043.2)
COBISS.SI-ID:2075044 New window
NUK URN:URN:SI:UM:DK:XOHSZSGK
Publication date in DKUM:23.03.2015
Views:1845
Downloads:131
Metadata:XML DC-XML DC-RDF
Categories:FZV
:
ZALOŽNIK, Vanja, 2015, MODEL REGULACIJE ENCIMA FOSFATAZE LAHKIH VERIG MIOZINA V RAZVOJU SILE V GLADKIH MIŠICAH [online]. Master’s thesis. Maribor : V. Založnik. [Accessed 8 April 2025]. Retrieved from: https://dk.um.si/IzpisGradiva.php?lang=eng&id=47158
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Secondary language

Language:English
Title:A MODEL OF MYOSIN LIGHT CHAIN PHOSPHATASE REGULATION IN THE PROCESS OF FORCE DEVELOPMENT IN SMOOTH MUSCLES
Abstract:In this master thesis we study key mechanisms for the development of force in smooth muscle cells (GMC). The time-course of force development in response to cholinergic stimulation of smooth muscles has two stages. In the first stage, in the time interval of one minute, the force rises up to 80-90% of the maximum force values. In the second stage, in the time interval of thirty minutes, the force develops for further 10-20% of maximum force values. The thesis is mainly focused to the second - slower stage in the development of force in smooth muscle cells. Based on the behaviours of the enzyme myosin light chain phosphatase (MLCP) and its role in the process of the airway smooth muscle contraction, we upgrade the existing model to simulate the calcium dependent time evolution of force development. The model was upgraded so that we explicitly modelled the impact of Rho kinase (ROCK) on the inhibition of the catalytic subunit (PP1c) of the MLCP enzyme via phosphorylation of the protein CPI-17. The model also includes the time course of phosphorylation of two threonine residues (T696 and T853) on the regulatory subunit (MYPT1) of the enzyme MLCP, which is based on the measured dependence. In the model we assume that all three of these elements, CPI-17, T696 and T853, inhibit the catalytic unit PP1c. Their inhibitory effect is modelled with a reversible competitive inhibition. The model is based on the assumption that all three phosphorylation sites: one in the phosphorylated protein CPI-17 and two at the phosphorylation sites T696 and T853 in the regulatory subunit MYPT1, interact with the catalytic subunit of PP1c on the same enzyme MLCP, and in this way reduce its activity. With the present model, we can explain further increase of force within the second stage of force development for additional 10-20%. The model simulates the effect of the inhibitor of the enzyme ROCK, as if ROCK is hypothetically involved only in the process of phosphorylation of the protein CPI-17, as well as for the example, as if is involved in both processes, i.e. of phosphorylation of the protein CPI-17 as well as of phosphorylation of threonine residues T696 and T853 on MYPT1. Based on the model, the second proposed mechanism is more likely to be expected. The model estimated that the contribution of ROCK to the phosphorylation of T696 and T853 on a long time scale might be 70%. With the present model we can fully confirm our hypotheses, and at the same time form new ones.
Keywords:smooth muscle cell, mathematical model, inhibition, force development, calcium, enzyme kinetics


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