Utjecaj TO901317 na procesiranje proteina APP u staničnom modelu bolesti Niemann Pick tipa C

master's thesis

• Title (english): Effects of TO901317 on APP processing in cellular model of Niemann Pick type C disease
• Author: Jelena Živković
• Mentor: Jasminka Štefulj (mentor)
• Mentor: Nada Oršolić (mentor)
• Committee member: Nada Oršolić (predsjednik povjerenstva)
• Committee member: Jasminka Štefulj (član povjerenstva)
• Committee member: Jasna Lajtner (član povjerenstva)
• Committee member: Božena Mitić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2011-05-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Poznato je da je kolesterol i njegovo nakupljanje povezano sa razvojem Alzheimerove bolesti. Jetreni receptori X (LXR) djeluju poput senzora kolesterola te modificiraju ekspresiju gena uključenih u njegov transport, katabolizam i eliminaciju što ih čini potencijalnim, novim metama u proučavanju veze kolesterola i Alzheimerove bolesti. Danas se sve više proučavaju sintetički ligandi receptora LXR, a jedan od najistraživanijih je TO901317. Cilj ovog rada bio je istražiti utjecaj sintetskog liganda receptora LXR (TO901317) na procesiranje proteina APP u staničnom modelu bolesti NPC. Pokusi su se provodli na stanicama sa stabilno deletiranim genom NPC1 (CHO-NPC1-/-), te paralelno na parentalnim stanicama divljeg tipa (CHOwt). Rezultati pokazuju da tretmanom stanica sa TO901317 dolazi do aktivacije receptora LXR što vodi do povećane transkripcije gena koji kodiraju transmembranske prenosioce kolesterola. Također, pokazalo se da TO901317 ima određeni utjecaj na procesiranje proteina APP, na endogenoj i egzogenoj razini te uzrokuje trend snižavanja ili povećavanja razine određenih proteina. Ovi rezultati ukazuju na efekte koje tretman sintetskim ligandom TO901317 ima na stanice te upućuje na to da bi se ovakvim terapijama moglo doći do povećavanja α- sekretazne aktivnosti, a time i snižavanja β- sekretazne aktivnosti te sprječavanja nakupljanja peptida Aβ.

Abstract (english)

It is known that cholesterol and its accumulation is associated with the development of Alzheimer's disease. Liver X receptors (LXR) act as cholesterol sensors and modify the expression of genes involved in its transport, catabolism and elimination, which makes them a potential, new targets in the study of the relationship of cholesterol and Alzheimer's disease. Today, more and more researches are examining synthetic LXR receptor ligands, and one of the most studied is TO901317. The aim of this study was to investigate the effects of synthetic LXR ligand receptor (TO901317) on the processing of APP protein in the cell model of NPC disease. Experiments were conducted on the parental wild-type cells (CHOwt )and on the cells with stably deleated NPC1 gene (CHO-NPC1-/ -) . The results show that treatment of cells with TO901317 induced activation of LXR receptors, which led to increased transcription of genes that encode transmembrane transporters of cholesterol. Also, it appeares that TO901317 has an impact on the processing of APP protein, on the endogenous and exogenous levels and causes a trend of increasing or decreasing levels of certain proteins. These results indicate that the treatmen with synthetic ligand TO901317 does have an effect on the treated cells, and also suggest that these therapies could lead to an increase of α-secretase activity and thus lower the β-secretase activitiy, which could possibly prevent the accumulation of Aβ peptide.

• Keywords: protein prekursor amiloida (APP); amiloid- β; kolesterol; jetreni receptori X (LXR); Alzheimerova bolest; bolest Niemann-Pick tipa C
• Keywords (english): amyloid precursor protein (APP); amyloid- β; cholesterol; liver X receptors (LXR); Alzheimer's disease; Niemann-Pick type C disease
• Language: croatian
• URN:NBN: urn:nbn:hr:217:012920
• Study programme: Title: Experimental Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra eksperimentalne biologije (magistar/magistra eksperimentalne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Access restricted to students and staff of home institution
• Created on: 2017-05-03 12:02:49