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Uloga interakcije receptora za fibroblastni faktor rasta sa neuralnim ćelijskim adhezionim molekulom u fibrozi bubrega

dc.contributor.advisorMarković-Lipkovski, Jasmina
dc.contributor.otherRadojević Škodrić, Sanja
dc.contributor.otherNaumović, Radomir
dc.contributor.otherMüller, Gerhard A.
dc.creatorŽivotić, Maja
dc.date.accessioned2020-09-25T15:01:35Z
dc.date.available2020-09-25T15:01:35Z
dc.date.issued2019-03-01
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7578
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:22497/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=512499380
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/17423
dc.description.abstractProgression of chronic kidney disease (CKD) remains an unsolved problem in clinical nephrology since approaches to reverse or repair chronic renal injury are not yet available. Independent of the underlying disease, loss of functional kidney parenchyma and tubulo-interstitial fibrogenesis are commonly observed when kidney injury progresses towards CKD. In this regard, epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells (TECs) and consecutive G2/M arrest have been shown to determine maladaptive kidney repair in response to injury, ultimately associated with renal fibrogenesis and progression into CKD. Transforming growth factor β1 (TGF-β1) is considered as a key mediator of intrarenal EMT program and renal fibrosis. Neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor (FGFR) signaling during EMT program have already been described and it has been noticed that both molecules are fundamental for EMT program in vitro. However, their cross-talk has been widely studied mainly in neural tissues and cancer cells, but there is a lacking of evidence for the contribution of their interplay to fibrogenesis, although several studies confirmed that both molecules can be separately involved in such process. Moreover, FGFR has been widely studied in many fields of research, including fibrosis, whereas NCAM contribution to renal fibrogenesis has been only suggested by two research groups (including our team). Thus, it encouraged us to investigate aforementioned molecules in human kidneys and to evaluate their significance in fibrotic response within the renal interstitial compartment. For the first time, here we present a functional significance of NCAM and FGFR co-operation in the induction of renal fibrosis, mediated by TGFβ-1. Material and methods In order to achieve goals of the study, we examined human kidney biopsy samples and performed cell culture experiments to clarify functional significance of NCAM/FGFR1 signaling in model of renal fibrosis. Immunostaining (immunohistochemistry and immunofluorescence) was performed to detect NCAM expressing cells in human kidneys in order to further characterize these cells and to label them for laser capture microdissection (LCM) which allows pure NCAM+ cells collecting for the subsequent qRT-PCR and gene expression analysis. Moreover, clinical relevance of both NCAM expressing renal interstitial cells and TGFβ-1 downstream effectors detection in human kidney biopsies were also examined. By using an established model of EMT program in human proximal tubular epithelial cells (HK- ii 2 cells) in response to TGF-β1 (10ng/mL) exposure, NCAM/FGFR1 signaling responses were analyzed by light microscopy, immunolabeling, qRT-PCR and scratch assays...en
dc.description.abstractProgresija hronične bubrežne insuficijencije predstavlja gotovo nerešiv problem kliničke nefrologije, imajući u vidu da su terapijski postupci koji bi doveli do zaustavljanja ili reverzibilnosti hroničnih oštećenja parenhima bubrega još uvek nedostupni. Sva hronična oboljenja bubrega dovode do progresivnog gubitka funkcionalnog parenhima i tubulointersticijske fibroze, indukujući pojavu hronične bubrežne insuficijencije. U tom pogledu, smatra se da je supstrat nemogućnosti regeneracije oštećenog parenhima bubrega zapravo fenomen epitelno-mezenhimne transformacije (EMT) sa sledstvenim G2/M zastojem u fazi ćelijskog ciklusa koji dovodi do nastanka fibroze i progresije hronične bubrežne insuficijencije. Smatra se da je glavni medijator EMT programa i fibroze u bubregu transformišući faktor rasta β1 (TGF-β1). Opisano je da se tokom EMT programa indukuje ekspresija neuralnog ćelijskog adhezionog molekula (NCAM) i receptora za fibroblastni faktor rasta (FGFR), koji imaju važnu ulogu u in vitro EMT. Međutim, značaj međusobnih interakcija NCAM i FGFR molekula do sada je prevashodno ispitivan u neuralnom tkivu i različitim malignim oboljenjima, dok nema podataka o značaju ovih interakcija tokom procesa fibroze, iako je nekoliko studija potvrdilo da individualno NCAM i FGFR molekul mogu biti uključeni u ovaj proces. Štaviše, FGFR je izučavan u mnogim patološkim procesima, uključujući i fibrozu, dok je povezanost NCAM molekula sa procesom fibroze u bubregu sugerisana od strane samo dva istraživačka tima (uključujući i naš). Stoga smo poželeli da ispitamo prethodno pomenute molekule u bubrezima čoveka i da procenimo njihov značaj u procesu fibrogeneze. Po prvi put, u ovoj studiji prikazujemo funkcionalni značaj NCAM/FGFR interakcija u indukciji fibroze bubrega, posredovanoj TGF-β1. Materijal i metode U svrhu ispitivanja zadatih ciljeva studije, korišćeni su uzorci humanih biopsija bubrega kao i eksperimenti na ćelijskim kulturama kako bi se razjasnio funkcionalni značaj NCAM/FGFR1 signalnog puta u modelu fibroze bubrega. Primenjene su imunohistohemisjke i imunofluorescentne tehnike detektovanja NCAM eksprimirajućih ćelija sa ciljem njihove bolje krakterizacije i vizuelizacije, kao i radi sprovođenja laserske mikrodiskcije (LCM) koja omogućava sakupljenje izolovanih NCAM+ ćelija za dalja ispitivanja genske ekspresije metodom real-time RT-PCR (qRT-PCR). Takođe, ispitan je klinički značaj prisustva NCAM+ ćelija u intersticijumu bubrega kao i značaj detekcije nishodnih efektora TGF-β1 v signalnog puta u biopsijskim uzorcima...sr
dc.formatapplication/pdf
dc.languageen
dc.publisherУниверзитет у Београду, Медицински факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175047/RS//
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectNCAMsr
dc.subjectNCAM, FGFR, PD173074, fibrozaen
dc.subjectFGFRsr
dc.subjectPD173074sr
dc.subjectfibrosissr
dc.titleThe role of interaction between fibroblast growth factor receptor and neural cell adshesion molecule in renal fibrosisen
dc.title.alternativeUloga interakcije receptora za fibroblastni faktor rasta sa neuralnim ćelijskim adhezionim molekulom u fibrozi bubregasr
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/65429/IzvestajKomisije23246.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/65428/Disertacija.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_17423


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