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Physicochemical aspects of rhythmicity
in neuroendocrine systems

Project Description

The main concept involved in proposed investigation is to use the nonlinear feedback inherent to neuroendocrine systems, and to use their sensitivity towards external perturbations, with aim to develop new system of control over dynamic states of the organism as a whole.

Feedback loops within neuroendocrine systems are fundamental property of life associated with almost all processes responsible for survival of living systems. Often, they emerge as biological rhythmicity of various periods, thus creating control subsystems with flexible dynamic recognized as HPA axis, HPT axis, etc. Our previous investigation resulted in several variants of the HPA axis model, enabling numerical simulation of wide spectrum of behaviour, including stress response or drug abuse behaviour. Used stoichiometric network model (or, simply, reaction model) explained strong sensitivity of various stress responses to small changes in the moment of drug implementation.

Hence, our discovery opened the doors for creating a quite new strategy of medicine application during the treatments of various illnesses. As a result of high sensitivity of a nonlinear feedback within a neuroendocrine system, dosage of applied drugs could be significantly decreased with preserved efficiency. To achieve an advance in this direction, we intend to further develop stoichiometric network model of the HPA axis with particular aim to decouple nonlinear feedback steps into more realistic feedback loops.

Moreover, we also intend to give the completely new model of the HPT axis Finally, reactivity as well as the influence on dynamic states of the main components from these neuroendocrine systems will be tested experimentally in oscillating reactions realised in closed and open reactors, with main goal to narrow the range of admissible parameter values for proposed models of neuroendocrine systems. Mentioned components will be extracted from natural sources and determined by numerous physicochemical methods.

Objectives

Having long experience in nonlinear dynamics of reaction systems [ - ], in the proposed Project (in rest of the text: Project NES) we are focused on the most intriguing property of the metabolic processes, the oscillatory dynamics based on their feedback loops, as an evolutionary mechanism for surviving after any type of stress (perturbation). In particular, we intend to resolve the role of positive and negative feedback steps in the already postulated and successfully applied model of the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis, and furthermore, propose the completely new reaction model of the hypothalamic-pituitary-thyroid (HPT) axis (See Figure 1).

Figure 1. Schematic presentation of HPA and HPT axis

To that purpose we need to extend our knowledge based on experimental and theoretical investigations of related subsystems and interactions of essential species in them. Thus, we need to examine the reaction activity of the species that exist in HPA and HPT axis and related models such as cortisol (the main hormone of HPA axis) and tyrosine (the most important constituent of thyroid hormones). Moreover, to mentioned purpose we need to extend our experimental and theoretical knowledge related to examinations of reaction mechanisms, in general.

More specific objective of our investigation will be to adjust the proposed models for HPA and HPT axis to the level where they will enable us to predict neuroendocrine response under homeostatic and stressed conditions as well as under conditions of some dynamical diseases.

1 S. Jelić, Ž. Čupić and Lj. Kolar-Anić, (2005) Mathematical modeling of the hypothalamic-pituitary-adrenal system activity, Mathematical biosciences, 197 (2): 173–187
2 V. M. Marković, Ž. Čupić, V. Vukojević and Lj. Kolar-Anić, (2011) Predictive modelling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress, Endocrine Journal, 58 (10): 889-904
3 V. M. Marković, Ž. Čupić, S. Maćešić, A. Stanojević, V. Vukojević and Lj. Kolar-Anić, (2016) Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis, Mathematical Medicine and Biology, 33 (1): 1–28
4 Ž. Čupić, A. Stanojević, V. M. Marković, Lj. Kolar-Anić, L. Terenius and V. Vukojević, (2017) The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations, Addiction biology, 22 (6): 1486-1500
5 O. A. Abulseoud, M. C. Ho, D.- S. Choi, A. Stanojević, Ž. Čupić, Lj. Kolar-Anić and V. Vukojević, (2017) Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modelling, PloS One, 12 (5): e0177551
6 Ž. Čupić, S. Maćešić, K. Novakovic, S. Anić and Lj. Kolar-Anić, (2018) Stoichiometric network analysis of a reaction system with conservation constraints, Chaos, 28 (8): 083114
7 J. Maksimović, Ž. Čupić, N. Manojlović,·A. Đerić, S. Anić and Lj. Kolar-Anić, (2020) Bray–Liebhafsky oscillatory reaction as the matrix system for the kinetic determination of microquantities of alizarin and purpurin, Reaction Kinetics, Mechanisms and Catalysis, 130 (2): 655–668

Work Packages (WPs)

  • WP1 (Project management and promotion – coordinated by the PI, Željko Čupić)

  • WP2 (Stoichiometric modelling of the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis – coordinated by the P6, Stevan Maćešić)

  • WP3 (Experimental and theoretical analysis of physicochemical oscillators – coordinated by the P7, Jelena Maksimović)

  • WP4 (Natural phenolic compounds as potential modulators of neuroendocrine system function– coordinated by the P2, Nedeljko Manojlović)

  • WP5 (Dissemination of project results through education and organization of scientific meetings – coordinated by the P4, Ana Ivanović-Šašić)