Matematični model vpliva cirkadiane ure na biosintezo holesterola

Magdevska, Lidija (author), Moškon, Miha (mentor), Mraz, Miha (co-mentor)

V preteklosti je bilo izpeljanih le nekaj matematičnih modelov biosinteze holesterola, čeprav so biokemijske reakcije, ki sestavljajo ta proces, dobro znane. Slabše znano in s stališča uporabe v medicini bolj zanimivo je, kako sintezo holesterola regulirajo drugi celični procesi, saj ti predstavljajo možne tarče za zdravljenje bolezni, ki so posledica previsokih ali prenizkih koncentracij holesterola v celicah. Celice holesterol nujno potrebujejo, saj ima ključno vlogo pri obnavljanju celične membrane in omogoča njeno selektivno propustnost, vendar se pri previsokih koncentracijah začnejo zastrupljati. Eden izmed celičnih procesov, za katerega je znano, da vpliva na biosintezo holesterola, je cirkadiana ura. To je skupek proteinov, ki regulira dnevno-nočni ritem ostalih procesov v celici. Eksperimentalno so pokazali, da se sočasno izbitje cirkadianih genov ROR$\alpha$ in ROR$\gamma$ manifestira v spremenjeni sintezi holesterola, prav tako tudi izbitje cirkadianega gena Rev-Erb. Predvideva se, da tako proteini iz družine ROR kot tudi proteini iz družine Rev-Erb vplivajo na izražanje gena Insig2, pri čemer eni njegovo izražanje pospešujejo, drugi pa zavirajo. V delu izpeljemo sistem navadnih diferencialnih enačb, ki opisuje vpliv cirkadianih genov ROR in RevErb na biosintezo holesterola. Sistem rešimo numerično in pokažemo, da se rešitev sklada z eksperimentalno pridobljenimi rezultati. Vzpostavljeni model lahko olajša postavljanje hipotez o natančnejših mehanizmih vpliva cirkadiane ure na biosintezo holesterola in s tem zmanjša stroške načrtovanja in izvedbe eksperimentov, s katerimi bi te hipoteze lahko potrdili.

• Language: Slovenian
• Keywords: računska biologija, cirkadiana ura, biosinteza holesterola, dinamični model
• Work type: Master's thesis/paper
• Organization: FMF - Faculty of Mathematics and Physics
• Year: 2019
• PID: 20.500.12556/RUL-109982
• UDC: 51-76
• COBISS.SI-ID: 18717785
• Publication date in RUL: 11.09.2019

Secondary language

• Language: English
• Title: A mathematical model describing the circadian clock influences on cholesterol biosynthesis

Abstract

Despite the biochemical reactions of cholesterol biosynthesis being well--known, few mathematical models describing this process have so far been developed. Less known and, from the medical perspective, more intriguing is the regulation of cholesterol synthesis by other cellular processes, as they could provide new drug targets for diseases that are caused by cellular cholesterol levels being too high or too low. Cells need cholesterol due to its role in maintaining the cellular membrane and enabling its selective permeability, but higher concentrations lead to cell poisoning. The circadian clock is known to be one of the cellular processes affecting cholesterol biosynthesis. It is a group of proteins regulating the day--night rhythm of other cellular processes. Experimentation has shown that simultaneous ROR$\alpha$ and ROR$\gamma$ gene knock--out results in the change of cholesterol synthesis. The same applies to the circadian gene Rev-Erb. Proteins from the ROR family along with those from the Rev-Erb family are believed to affect Insig2 gene expression with one family behaving as activators and the other as repressors. In this thesis we derive a system of ordinary differential equations describing the circadian effect of ROR and Rev-Erb genes to cholesterol biosynthesis. We solve the system numerically and show that it corresponds to experimental results. The developed model can be used to simplify stating hypotheses about specific mechanisms of the circadian clock's effect on cholesterol biosynthesis, thus lowering the planning and execution costs of experiments intended to test the hypothesis.

• Keywords: computational biology, circadian clock, cholesterol biosynthesis, dynamic model