Please use this identifier to cite or link to this item:
https://open.uns.ac.rs/handle/123456789/30164
DC Field | Value | Language |
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dc.contributor.advisor | Kostić Tatjana | - |
dc.contributor.author | Janjić Marija | - |
dc.contributor.other | Mimica-Dukić Neda | - |
dc.contributor.other | Kostić Tatjana | - |
dc.contributor.other | Matić Gordana | - |
dc.contributor.other | Andrić Silvana | - |
dc.date.accessioned | 2020-12-14T17:53:43Z | - |
dc.date.available | 2020-12-14T17:53:43Z | - |
dc.date.issued | 2012-11-09 | - |
dc.identifier.uri | https://open.uns.ac.rs/handle/123456789/30164 | - |
dc.description.abstract | <p>Biosinteza testosterona, glavnog muškog polnog hormona, u Leydig-ovim ćelijama testisa je primarno regulisana cAMP signalnim putem, ali se i drugi signalni putevi uključuju kao modulatorni. Obzirom da nema preciznih podataka o učešću cGMP signalnog puta u regulaciji androgeneze Leydig-ovih ćelija, ova studija je dizajnirana da definiše: (1) funkcionalnost cGMP signalnog puta, kao i mehanizme preko kojih se ovaj signalni put upliće u regulaciju procesa sinteze testosterona; (2) funkcionisanje cGMP puta u uslovima poremećene homeostaze testosterona tj. eventualne mehanizme povratne sprege od testosterona na cGMP signalni puta u Leydig-ovim ćelijama testisa adultnih pacova. Homeostaza Leydig-ovih ćelija i funkcionalnost NO-cGMP signalnog puta je praćena korišćenjem pet in vivoekperimentalih modela: dva u kojima je mimikrirana poremećena homeostaza cGMP signalnog puta (akutni i hronični tretman Sildenafil-citratom, Vijagrom) i tri u kojima je mimikrirana poremećena homeostaza testosterona (androgenizacija; hipogonadalni-hipgonadizam; sistemska blokada androgenog receptora). Rezultati su pokazali da Leydig-ove ćelije ekspresuju funkcionalne komponente cGMP signalnog puta (GUCY1, GUCY2, PRKG1, PRKG2 i PDE5) i da cGMP stimuliše androgenezu Leydig-ovih ćelija povećavajući transport holesterola u mitohondrije preko PRKG1 zavisne fosforilacije StAR proteina. Akutni in vivotretman sa Sildenafil-citratom je povećao zapreminu TIF-a, kao i koncentraciju androgena u TIF-u, testikularnom tkivu i serumu, a ovaj stimulatorni efekat je ostvaren angažovanjem cGMP-PRKG1 signalnog puta. Hronični in vivo tretman Sildenafil-citratom je povećao nivo cirkulišućih androgena i bazalnu androgenu produkciju Leydig-ovih ćelija ukjučivanjem i cAMP i cGMP signalnih puteva i njihovom zajedničkom aktivacijom StAR proteina. Sa druge strane, visoki nivo sistemskog testosterona je smanjio membranski potencijal mitohondrija (∆ψm ), stimulisao ekspresiju pro-apoptotičke NOS2, a samim tim i produkciju NO, a inhibisao ekspresiju anti-apoptotičke PRKG1, što je uz povećanu razgradnju cGMP-a stimulacijom ekspresije PDE5, omogućilo prevladavanje pro-apoptotičnih nad anti-apoptočnim signalima i apoptozu Leydig-ovih ćelija. Sistemskom blokadom androgenih receptora poništeni su pro-apoptotički efekti testosterona. Sumirano, može se zaključiti da je cGMP signalni put u Leydig-ovim ćelijama adultnih pacova funkcionalan i da reguliše proces biosinteze testosterona, a da testosteron modulacijom NO-cGMP signalnog puta predstavlja potencijalni autokrini regulator testikularne anrogeneze i da u uslovima visokog nivoa sistemskog testosterona doprinosi uspostavljanju „androgene homeostaze“ preko regulacije brojnosti populacije Leydig-ovih ćelija.</p> | sr |
dc.description.abstract | <p>Biosynthesis of testosterone, the main male sex hormone, in testicular Leydig cells is dominantly regulated by cAMP signaling but also several other pathways also contribute to this process including nitric oxide (NO)-cGMP signaling pathway. Although NO-cGMP signaling pathway is operative, its presence and the role in steroidogenesis have been incompletely characterized. For that reason, this study was designed to define: (1) status of cGMP signaling pathway in Leydig cells, and the mechanism by which cGMP could control steroidogenesis, as well as, (2) the possible autocrine role of testosterone on NO-cGMP pathway in Leydig cells. To addressed these issue several different experimental approaches were used: two in vivomodels that mimicked disturbed homeostasis of NO-cGMP signaling pathway (acute and chronic treatment with the inhibitor of phosphodiesterase 5 (PDE5), Sildenafil citrate, Viagra) and three in vivomodels that mimicked disturbed homeostasis of testosterone (treatment of eugonadal rats with testosterone enanthate; an experimental model of hypogonadotropic hypogonadism together with testosterone replacement; and treatment with androgen receptor antagonist). Additionally ex vivostudies on purified Leydig cells were applied. The results showed that in Leydig cells expressed functional components of cGMP signaling pathway (GUCY1, GUCY2, PRKG1, PRKG2 and PDE5) and that cGMP stimulates androgenesis in Leydig cells by increasing transport of cholesterol into the mitochondria through PRKG1-dependent StAR protein phosphorylation. Acute in vivoInhibition of PDE5 increased TIF volume, as well as, concentration of androgens in TIF, testicular tissue and serum, and this stimulatory effect was achieved by engaging cGMP-PRKG1 signaling pathway. Chronic in vivo PDE5 inhibition increased the level of circulating androgens and basal androgen production of Leydig cells by engagement of cAMP- and cGMP-signaling pathways and their mutual activation of StAR protein. Data obtained in second part provide novel evidence for the role of testosterone in the down-regulation of Leydig cell functionality by regulating the NO-cGMP signaling pathway. The high systemic testosterone level reduced mitochondrial <br />membrane potential (∆ψm ), stimulated expression of pro-apoptotic NOS2, and thus the production of NO, but inhibited expression of anti-apoptotic PRKG1 and increased degradation of cGMP by stimulation of PDE5 expression. This signaling scenario leads to decreased Leydig cell steroidogenesis and was associated with increased apoptosis of Leydig cells. Systemic androgen receptor blockade abrogated the pro-apoptotic effects of testosterone. Furthermore, in hypogonadal animals with low serum testosterone, the NOS2 protein level and NO production from Leydig cells were significantly reduced. The ex vivo results indicate that testosterone gradually up-regulated Nos2 gene expression and NO production in primary Leydig cell cultures. These findings suggest that up-regulation of Nos2gene expression is a direct effect of testosterone on Leydig cells.In summary, it can be concluded that cGMP signaling pathway is functional in Leydig cells of adult rats and is involved in regulation of testosterone biosynthesis. Testosterone, on the other side, acts as autocrine regulator of testicular androgenesis and important regulator of abundance of Leydig cell population.</p> | en |
dc.language.iso | sr (latin script) | - |
dc.publisher | Univerzitet u Novom Sadu, Prirodno-matematički fakultet u Novom Sadu | sr |
dc.publisher | University of Novi Sad, Faculty of Sciences at Novi Sad | en |
dc.source | CRIS UNS | - |
dc.source.uri | http://cris.uns.ac.rs | - |
dc.subject | cGMP, PRKG, PDE5, Leydig-ove ćelije, testosteron, StAR | sr |
dc.subject | cGMP, PRKG, PDE5, Leydig cells, steroidogenesis, testosterone, StAR | en |
dc.title | Signalni put cikličnog guanozin monofosfata u Leydig-ovim ćelijama | sr |
dc.title | Cyclic guanosine monophosphate signaling pathway in Leydig cells | en |
dc.type | Thesis | en |
dc.identifier.url | https://www.cris.uns.ac.rs/record.jsf?recordId=90074&source=BEOPEN&language=en | en |
dc.identifier.externalcrisreference | (BISIS)90074 | - |
dc.source.institution | Prirodno-matematički fakultet u Novom Sadu | sr |
item.grantfulltext | none | - |
item.fulltext | No Fulltext | - |
Appears in Collections: | PMF Teze/Theses |
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