Modeling of the stress influence on the hypothalamo-pituitaryadrenal system dynamics.

physical chemistry / biophysical chemistry and dynamics of non-equilibrium processesU ovom doktorskom radu razmatrano je modelovanje hipotalamo-hipofiznoadrenalnog (HPA) sistema, veoma složenog i važnog neuroendokrinog sistema, bitnog za održavanje svakodnevnih fizioloških funkcija organizma, i presudnog za odgovor organizma na dejstvo različitih stresora, odnosno u reakciji „bori se ili beži“. Cilj rada je modelovanje uticaja stresa na dinamiku HPA sistema. U tu svrhu postavljen je stehiometrijski model koji opisuje dnevni ritam sekrecije hormona ovog sistema, analizirana stabilnost sistema diferencijalnih jednačina koje slede iz njega i ispitivana simulacija rada ovog sistema pri dejstvu stresora. U složenom biološkom sistemu, kao što je HPA sistem, gde nisu još u potpunosti razjašnjeni svi procesi i mehanizmi funkcionisanja, a ni sve nije merljivo, matematičko modelovanje je korisno, posebno ako bi pomoglo da se izdvoje i definišu individualne karakteristike na osnovu kojih bismo mogli predvideti kako bi pojedinac reagovao u različitim situacijama. U poglavlju 1, izložen je opis hipotalamo-hipofizno-adrenalnog sistema. Krajnji proizvod ovog sistema, hormon kortizol (kod čoveka) i kortikosteron (kod glodara), pozitivnim i negativnim povratnim spregama reguliše sopstveno stvaranje, odnosno aktivnost čitavog sistema. U poglavlju 2, dat je kratak prikaz nekoliko do sada u stručnoj literaturi objavljenih modela ovog sistema i istaknuta razlika izmedju stehiometrijskih i nestehiometrijskih modela. U poglavlju 3, izložen je model razmatran u ovom radu, koji opisuje ritam rada hipotalamo-hipofizno-adrenalnog sistema i analizirana je stabilnost datog modela primenom metode stehiometrijske mrežne analize. U poglavlju 4 prikazani su rezultati numeričkih simulacija rada HPA sistema pri akutnom i hroničnom dejstvu stresora, dobijeni na osnovu razmatranog modela. Svrha ovog rada nije bila da se formuliše matematički model HPA sistema koji bi opisivao sve procese prisutne u ovom složenom sistemu, jer čak i kada bi to bilo moguće uraditi, dobijeni model bi bio preobiman i davao bi malo značajnih odnosa u sistemu. Umesto toga, cilj nam je bio formulisanje minimalnog modela koji bi dovoljno verno prikazao suštinski bitne interakcije i predvideo ponašanje sistema pri zadatim uslovimaIn this doctoral dissertation modelling of the hypothalamic-pituitary-adrenal (HPA) system, a very complex and important neuroendocrine system, relevant for maintenance of everyday physiological functions of an organism, and crucial in response to different stressors, i.e. in “fight or flight’ reaction, is considered. The aim of this work is modelling of the influence of stressors on the HPA system dynamics. With this intention, a stoichiometric model was made, to describe the daily rhythm of hormonal secretion,stability of corresponding differential equations system was analyzed, and functioning of this system under stress was simulated In complex biological systems, such as the HPA system, where all underlying processes and mechanisms are not fully understood jet, and not everything could be measured, mathematical modelling is useful, especially if it could lead to, and define individual personal characteristics, based on which we could estimate how would a person react in different situations. In chapter 1, description of the HPA system is given. Final products of this system, hormones cortisol (in humans), and corticosterone (in rats), through different positive and negative feedback actions regulate their own production, i.e. activity of this system. In chapter 2, a short description of several models of this system published in the literature so far, and a difference between stoichiometric and non-stoichiometric models is specified. In chapter 3, the model of the HPA system functioning considered in this work is described, and stability of this model is analyzed using stoichiometric network analysis. In chapter 4, results of numerical simulations of the HPA system functioning, under acute and chronic stress conditions, obtained based on the model considered, are given. The aim of this work wasn’t to formulate a mathematical model that could describe all processes present in this complex system, because even if that could be possible, resulting model would be too large and it would not give enough important relations in the system. Instead of that, our aim was to formulate a minimal model that could describe crucial interactions in the system, and predict the behaviour of the system in given condition