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The association of glucocorticoid receptor phosphorylation status and behavior of rats of both sexes in neuroinflammatory model of depression

dc.contributor.advisorAdžić, Miroslav
dc.contributor.otherNedeljković, Nadežda
dc.contributor.otherLukić, Iva
dc.creatorBrkić, Željka N.
dc.date.accessioned2020-03-09T09:12:35Z
dc.date.available2020-03-09T09:12:35Z
dc.date.available2020-07-03T08:15:21Z
dc.date.issued2019-12-27
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/12180
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7351
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:21603/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51943439
dc.description.abstractMedijatori inflamacije imaju značajnu ulogu u patogenezi depresije. Jedan od načina na koje inflamacija utiče na nastanak ovog oboljenja jeste putem uticaja na hipotalamo-hipofizno-nadbubrežnu (HPA) osu i krajnje produkate aktivnosti ove ose, glukokortikoide. Glukokortikoidi se u ćelijama vezuju za glukokortikoidni receptor (GR), ligand-zavisan transkripcioni faktor, koji nakon vezivanja glukokortikoida prelazi iz citoplazme u jedro i mitohondrije, gde reguliše ekspresiju velikog broja gena. Aktivnost GR-a je regulisana i kompleksnim obrascem fosforilacija koje mogu da utiču na transkripcionu aktivnost ovog receptora. Pored toga što modulišu ekspresiju jedarnih gena, GR i njegove fosfoforme utiču i na mitohondrijske procese, i na taj način mogu da budu uključeni u proces apoptoze. Značajnu ulogu u nastanku ovog oboljenja ima i pol – kod žena se depresija javlja duplo češće nego kod muškaraca. Uzimajući u obzir navedene podatke, u ovoj tezi je ispitan uticaj sedmodnevnog tretmana inflamatornim agensom, lipopolisaharidom (LPS), na nivoe i fosforilacioni status GR-a u citosolu, jedru i mitohondrijama prefrontalnog korteksa (PFC) i hipokampusa mužjaka i ženki pacova Wistar soja koji pokazuju depresivno ponašanje. Takođe, u citosolu i jedru su praćeni i nivoi košaperona GR-a i kinaza uključenih u njegovu forforilaciju, dok su u citosolu i mitohondrijama praćeni nivoi nekoliko kaspaza i članova BCL-2 proteinske porodice uključenih u regulaciju apoptoze. Dalje, kako bi se utvrdili efekti promena u fosforilaciji na gensku ekspresiju, praćeni su i nivoi iRNK nekoliko jedarnih i mitohondrijskih gena koji su regulisani ovim receptorom i koji su uključeni u parofiziologiju depresije. Rezultati ove studije su pokazali da promene uočene u glukokortikoidnoj signalizaciji izazvane LPS-om utiču na procese uključene u nastanak depresije na tkivno- i polno- specifičan način. Kod mužjaka, poremećaji u glukokortikoidnoj signalizaciji su bili praćeni promenama koje ukazuju na smanjenu neuroplastičnost i neuroinflamaciju i povišenu oksidativnu fosforilaciju u PFC-u. Sa druge strane, promene u glukokortikoidnoj signalizaciji u hipokampusu su bile praćene promenama koje ukazuju na poremećenu serotoninsku neurotransmisiju i narušene neuroendokrine 7 precese...sr
dc.description.abstractof the ways in which inflammation can influence the onset of this disease is by affecting the activity od hypothalamic-pituitary-adrenal (HPA) axis, and the levels of glucocorticoids, the end-products of the activity of this axis. Glucocorticoids bind to the glucocorticoid receptor (GR), a ligand-dependent transcription factor that, upon glucocorticoid binding, translocates from the cytoplasm to the nucleus, where it regulates the expression of a large number of genes. GR activity is also regulated by a complex pattern of phosphorylations that affect the transcriptional activity of the receptor. In addition to modulating the expression of nuclear genes, GR and its phosphoforms also affect mitochondrial processes, and may be involved in the process of apoptosis. Sex also plays a significant role in the onset of the disease - in women, depression occurs twice as often as in men. Considering these data, in this study we investigated the effect of the seven-day treatment with an inflammatory agent, lipopolysaccharide (LPS), on the levels and phosphorylation status of GR in the cytosol, nucleus and mitochondria of the prefrontal cortex (PFC) and hippocampus of male and female Wistar rats with depressive-like behavior. We also measured the levels of GR co-chaperones and kinases involved in its phosphorylation in cytosol and nucleus, together with the levels of several caspases and members of the BCL-2 protein family involved in the regulation of apoptosis in the cytosol and mitochondria. In order to determine the effects of changes in phosphorylation on gene expression, the mRNA levels of several nuclear and mitochondrial genes regulated by this receptor and involved in the patophysiology of depression were also measured. The results of this study showed that changes observed in glucocorticoid signaling induced by LPS were associated with processes involved in the onset of depression in a tissue- and sex-specific manner. In males, alterations in glucocorticoid signaling were followed by alterations that suggest decreased neuroplasticity and 9 neuroinflammation, increased oxidative phosphorylation in PFC...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectlipopolisaharid, depresivno ponašanje, pol, prefrontalni korteks, hipokampus, glukokortikoidni receptror, mitohondrijski signalingsr
dc.subjectlipopolysaccharide, depressive-like behavior, sex, prefrontal cortex, hippocampus, glucocorticoid receptor phosphorylation, mitochondrial signalingen
dc.titlePovezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresijesr
dc.title.alternativeThe association of glucocorticoid receptor phosphorylation status and behavior of rats of both sexes in neuroinflammatory model of depressionen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/3602/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/3603/IzvestajKomisije22313.pdf


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