TY  - JOUR
AU  - Kolar-Anić, Ljiljana
AU  - Čupić, Željko
AU  - Maćešić, Stevan
AU  - Ivanović-Šašić, Ana
AU  - Dietrich, Johannes
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/6416
AB  - The synthesis of thyroid hormones in the hypothalamic-pituitary-thyroid (HPT) axis was studied. For this purpose,
a reaction model for HPT axis with stoichiometric relations between the main reaction species was
postulated. Using the law of mass action, this model has been transformed into a set of nonlinear ordinary
differential equations. This new model has been examined by stoichiometric network analysis (SNA) with the aim
to see if it possesses the ability to reproduce oscillatory ultradian dynamics founded on the internal feedback
mechanism. In particular, a feedback regulation of TSH production based on the interplay between TRH, TSH,
somatostatin and thyroid hormones was proposed. Besides, the ten times larger amount of produced T4 with
respect to T3 in the thyroid gland was successfully simulated. The properties of SNA in combination with
experimental results, were used to determine the unknown parameters (19 rate constants of particular reaction
steps) necessary for numerical investigations. The steady-state concentrations of 15 reactive species were tuned
to be consistent with the experimental data. The predictive potential of the proposed model was illustrated on
numerical simulations of somatostatin influence on TSH dynamics investigated experimentally by Weeke et al. in
1975. In addition, all programs for SNA analysis were adapted for this kind of a large model. The procedure of
calculating rate constants from steady-state reaction rates and very limited available experimental data was
developed. For this purpose, a unique numerical method was developed to fine-tune model parameters while
preserving the fixed rate ratios and using the magnitude of the experimentally known oscillation period as the
only target value. The postulated model was numerically validated by perturbation simulations with somatostatin
infusion and the results were compared with experiments available in literature. Finally, as far as we know,
this reaction model with 15 variables is the most dimensional one that have been analysed mathematically to
obtain instability region and oscillatory dynamic states. Among the existing models of thyroid homeostasis this
theory represents a new class that may improve our understanding of basic physiological processes and helps to
develop new therapeutic approaches. Additionally, it may pave the way to improved diagnostic methods for
pituitary and thyroid disorders.
PB  - Elsevier
T2  - Computers in Biology and Medicine
T1  - Modelling of the thyroid hormone synthesis as a part of nonlinear reaction mechanism with feedback
VL  - 160
SP  - 106980
DO  - 10.1016/j.compbiomed.2023.106980
ER  - 

@article{
author = "Kolar-Anić, Ljiljana and Čupić, Željko and Maćešić, Stevan and Ivanović-Šašić, Ana and Dietrich, Johannes",
year = "2023",
abstract = "The synthesis of thyroid hormones in the hypothalamic-pituitary-thyroid (HPT) axis was studied. For this purpose,
a reaction model for HPT axis with stoichiometric relations between the main reaction species was
postulated. Using the law of mass action, this model has been transformed into a set of nonlinear ordinary
differential equations. This new model has been examined by stoichiometric network analysis (SNA) with the aim
to see if it possesses the ability to reproduce oscillatory ultradian dynamics founded on the internal feedback
mechanism. In particular, a feedback regulation of TSH production based on the interplay between TRH, TSH,
somatostatin and thyroid hormones was proposed. Besides, the ten times larger amount of produced T4 with
respect to T3 in the thyroid gland was successfully simulated. The properties of SNA in combination with
experimental results, were used to determine the unknown parameters (19 rate constants of particular reaction
steps) necessary for numerical investigations. The steady-state concentrations of 15 reactive species were tuned
to be consistent with the experimental data. The predictive potential of the proposed model was illustrated on
numerical simulations of somatostatin influence on TSH dynamics investigated experimentally by Weeke et al. in
1975. In addition, all programs for SNA analysis were adapted for this kind of a large model. The procedure of
calculating rate constants from steady-state reaction rates and very limited available experimental data was
developed. For this purpose, a unique numerical method was developed to fine-tune model parameters while
preserving the fixed rate ratios and using the magnitude of the experimentally known oscillation period as the
only target value. The postulated model was numerically validated by perturbation simulations with somatostatin
infusion and the results were compared with experiments available in literature. Finally, as far as we know,
this reaction model with 15 variables is the most dimensional one that have been analysed mathematically to
obtain instability region and oscillatory dynamic states. Among the existing models of thyroid homeostasis this
theory represents a new class that may improve our understanding of basic physiological processes and helps to
develop new therapeutic approaches. Additionally, it may pave the way to improved diagnostic methods for
pituitary and thyroid disorders.",
publisher = "Elsevier",
journal = "Computers in Biology and Medicine",
title = "Modelling of the thyroid hormone synthesis as a part of nonlinear reaction mechanism with feedback",
volume = "160",
pages = "106980",
doi = "10.1016/j.compbiomed.2023.106980"
}

Kolar-Anić, L., Čupić, Ž., Maćešić, S., Ivanović-Šašić, A.,& Dietrich, J.. (2023). Modelling of the thyroid hormone synthesis as a part of nonlinear reaction mechanism with feedback. in Computers in Biology and Medicine
Elsevier., 160, 106980.
https://doi.org/10.1016/j.compbiomed.2023.106980

Kolar-Anić L, Čupić Ž, Maćešić S, Ivanović-Šašić A, Dietrich J. Modelling of the thyroid hormone synthesis as a part of nonlinear reaction mechanism with feedback. in Computers in Biology and Medicine. 2023;160:106980.
doi:10.1016/j.compbiomed.2023.106980 .

Kolar-Anić, Ljiljana, Čupić, Željko, Maćešić, Stevan, Ivanović-Šašić, Ana, Dietrich, Johannes, "Modelling of the thyroid hormone synthesis as a part of nonlinear reaction mechanism with feedback" in Computers in Biology and Medicine, 160 (2023):106980,
https://doi.org/10.1016/j.compbiomed.2023.106980 . .