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doctoral thesis
Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze
Zagreb: University of Zagreb, School of Medicine, 2022. urn:nbn:hr:105:172397
Šisl, Dino
University of Zagreb
School of Medicine

Institutional repository: Dr Med - University of Zagreb School of Medicine Digital Repository

Cite this document

Šisl, D. (2022). Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze (Doctoral thesis). Zagreb: University of Zagreb, School of Medicine. Retrieved from https://urn.nsk.hr/urn:nbn:hr:105:172397

Šisl, Dino. "Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze." Doctoral thesis, University of Zagreb, School of Medicine, 2022. https://urn.nsk.hr/urn:nbn:hr:105:172397

Šisl, Dino. "Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze." Doctoral thesis, University of Zagreb, School of Medicine, 2022. https://urn.nsk.hr/urn:nbn:hr:105:172397

Šisl, D. (2022). 'Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze', Doctoral thesis, University of Zagreb, School of Medicine, accessed 27 December 2024, https://urn.nsk.hr/urn:nbn:hr:105:172397

Šisl D. Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze [Doctoral thesis]. Zagreb: University of Zagreb, School of Medicine; 2022 [cited 2024 December 27] Available at: https://urn.nsk.hr/urn:nbn:hr:105:172397

D. Šisl, "Uloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze", Doctoral thesis, University of Zagreb, School of Medicine, Zagreb, 2022. Available at: https://urn.nsk.hr/urn:nbn:hr:105:172397

Metadata
TitleUloga signalnog puta Notch u jetrenim zvjezdolikim stanicama tijekom razvoja mišjeg modela jetrene fibroze
Title (english)The role of Notch signaling pathway in hepatic stellate cells in development of murine model of liver fibrosis
AuthorDino Šisl
MentorTomislav Kelava (mentor)
Committee memberDanka Grčević (predsjednik povjerenstva)
Committee memberDrago Batinić (član povjerenstva)
Committee memberNataša Kovačić (član povjerenstva)
GranterUniversity of Zagreb
School of Medicine
Zagreb
Defense date and country2022-12-15, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Clinical Medical Sciences
Clinical Immunology
Universal decimal classification
(UDC)		612 - Physiology
Abstract
U ovom radu istražili smo kako modulacija signalnog puta Notch u aktiviranim jetrenim zvjezdolikim stanicama (aHSC) utječe na razvoj fibroze koristeći dva životinjska modela, toksični model primjene CCl4 i kolestatski model prehrane s dodatkom spoja DDC. Pokazali smo da je signalni put Notch induciran tijekom razvoja fibroze. Zatim smo na transgeničnim miševima soja SMACreERT2+/-/Ai9 pokazali da se stanice koje bazalno izražavaju αSMA ne umnožavaju tijekom fibroze te da su glavni izvor miofibroblasta HSC. Pokusima na miševima soja SMACreERT2+/-/RBP-Jfl/fl i SMACreERT2+/-/RosaNICD1 pokazali smo da inhibicija ili pojačana aktivacija signalnog puta Notch u aHSC ne utječe na stupanj fibroze. Nadalje, pokazali smo da u miševa s pojačanom aktivnošću signalnog puta Notch dolazi do normalnog oporavka od fibroze po prestanku fibrogenog poticaja. U nedavno objavljenom sličnom istraživanju pokazano je da inhibicija signalnog puta Notch smanjuje razvoj fibroze, ali ono nije procijenilo mogućnost antifibrotičkog učinka samog tamoksifena. Stoga smo u završnoj fazi istraživanja istražili može li tamoksifen imati utjecaja na ishod fibroze jetre u kolestatskom modelu. Pokazali smo da tamoksifen ima antifibrotični učinak u kolestatskom modelu, a naša hipoteza je da je zaštitni učinak tamoksifena posredovan pojačanim izražavanjem Tgfβ i Il6 te smatramo da bi ovi signalni putevi trebali biti fokus daljnjih istraživanja.
Abstract (english)
We aimed to investigate how Notch signaling pathway modulation (inhibition and overactivation) affects the development of liver fibrosis. In the first experiment we have shown that Notch signaling pathway is induced in two fibrosis models, CCl4 application and DDCsupplemented feeding. Further, by using transgenic SMACreERT2+/-/Ai9 mice, we have shown that constitutionally αSMA-positive cells do not multiply during fibrosis and that the main source of αSMA-positive myofibroblasts must be hepatic stellate cells. By using SMACreERT2+/-/RBP-Jfl/fl and SMACreERT2+/-/RosaNICD1 mice we have shown that neither Notch inhibition nor its overactivation in activated hepatic stellate cells affects the degree of liver fibrosis. Furthermore, Notch overactivation had no effect on resolution of liver fibrosis once the fibrogenic stimulus was removed. A recently published article with a methodology similar to ours reported a lesser extent of fibrosis with Notch inhibition, but the possibility of confounding effect of tamoxifen remained open. Therefore, we decided to investigate whether tamoxifen itself affects fibrosis development in the DDC-model. Our results show that tamoxifen indeed has a protective role in the DDC-model and we hypothesize that the protective effect of tamoxifen might be mediated through Il6 and Tgfβ upregulation, suggesting these pathways as a primary focus for further research.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:105:172397
ProjectNumber: UIP-2017-05-1965
Title: Uloga Notch signalnog puta u patogenezi jetrene fibroze
Acronym: NOFIBRO
Leader: Tomislav Kelava
Jurisdiction: Croatia
Funder: HRZZ
Funding stream: UIP
Study programmeTitle: Biomedicine and Health Sciences
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
Type of resourceText
Extent92 str.
File originBorn digital
Access conditionsOpen access
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Created on2023-01-12 08:32:24