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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Uloga insulinskih i IGF1 receptora u regulaciji steroidogeneze i mitohondrijallne biogenze u Leydigovim ćelijama / The role of insulin and IGF1 receptors in regulation of teroidogenesis and mitochondrial biogenesis in Leydig cells

Radović Sava 31 May 2019 (has links)
<p>Leydig-ove&nbsp; ćelije&nbsp; testisa&nbsp; su&nbsp; primarno&nbsp; mesto&nbsp; sinteze mu&scaron;kih polnih hormona. Ovi hormoni su neophodani za reproduktivno,&nbsp; ali&nbsp; i&nbsp; za&nbsp; op&scaron;te&nbsp; zdravlje&nbsp; budući&nbsp; da&nbsp; su<br />ozbiljni zdravstveni problemi često povezani sa njihovom smanjenom produkcijom.&nbsp; Insulin i insulinu sličan faktor rasta&nbsp; 1,&nbsp; IGF1&nbsp; <em>(engl.</em>&nbsp; insulin&nbsp; like&nbsp; growth&nbsp; factor&nbsp; 1),&nbsp; i<br />signalizacija koju pokreću preko svojih receptora&nbsp; (INSR i IGF1R),&nbsp; su&nbsp; jedan&nbsp; od&nbsp; ključnih&nbsp; faktora&nbsp; koji&nbsp; reguli&scaron;u specifični razvoj tkiva, pa i samih gonada. Ipak,&nbsp; uloga&nbsp; i<br />mehanizmi&nbsp; delovanja&nbsp; ovih&nbsp; receptora&nbsp; u&nbsp; steroidogenim tkivima nisu&nbsp; u potpunosti&nbsp; poznati.&nbsp; Stoga je&nbsp; istraživanje&nbsp; uokviru ove&nbsp; doktorske&nbsp; disertacije&nbsp; koncipirano sa ciljem da se,&nbsp; na&nbsp; modelu&nbsp; prepubertalnih&nbsp; (P21)&nbsp; i&nbsp; adultnih&nbsp; (P80) mužjaka mi&scaron;eva sa kondicionalnom delecijom<em> Insr </em>i <em>Igf1</em>r gena&nbsp; u&nbsp; steroidogenim&nbsp; ćelijama&nbsp; (Insr/Igf1r-DKO), defini&scaron;e uloga INSR i IGF1R u regulisanju diferencijacije i&nbsp; steroidogene&nbsp; funkcije&nbsp; Leydig-ovih&nbsp; ćelija.&nbsp; Pored&nbsp; toga, mužjaci&nbsp; i&nbsp; ženke&nbsp; P21&nbsp; mi&scaron;eva&nbsp; sa&nbsp; istom&nbsp; delecijom&nbsp; su kori&scaron;ćeni&nbsp; za&nbsp; praćenje&nbsp; ekspresije&nbsp; glavnih&nbsp; markera mitohondrijalne&nbsp; biogeneze&nbsp; i&nbsp; fuzije/arhitekture&nbsp; u&nbsp; Leydigovim&nbsp; ćelijama,&nbsp; ovarijumima&nbsp; i&nbsp;&nbsp; nadbubrežnim&nbsp; žlezdama. Rezultati&nbsp; su&nbsp; potvrdili&nbsp; da&nbsp; delecija&nbsp; Insr&nbsp; i&nbsp; Igf1r&nbsp; u<br />steroidogenim&nbsp; tkivima&nbsp; utiče&nbsp; na&nbsp; diferencijaciju&nbsp; i funkcionalne karakteristike Leydig-ovih ćelija P21 i P80 mi&scaron;eva,&nbsp; upućujući&nbsp; na&nbsp; pojavu&nbsp; tzv.&nbsp; &bdquo;feminizacije&ldquo;.&nbsp; Broj<br />Leydig-ovih&nbsp; ćelija&nbsp; izolovanih&nbsp; iz&nbsp; P21&nbsp; i&nbsp; P80&nbsp; Insr/Igf1rDKO&nbsp; mi&scaron;eva&nbsp; bio&nbsp; je&nbsp; smanjen,&nbsp; a&nbsp; morfologija&nbsp; i ultrastruktura&nbsp; ovih&nbsp; ćelija&nbsp; izmenjene&nbsp; kod&nbsp; P21&nbsp; Insr/Igf1rDKO&nbsp; mi&scaron;eva.&nbsp; Steroidogeni&nbsp; kapacitet&nbsp; i&nbsp; aktivnost,&nbsp; kao&nbsp; i ekspresija&nbsp; glavnih&nbsp; elemenata&nbsp; steroidogene&nbsp; ma&scaron;inerije <em>(Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1&nbsp; i&nbsp; 6, Hsd17b3,</em><br /><em>Sf</em>1)&nbsp; bili su&nbsp; smanjeni&nbsp; u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1</em>r-DKO mi&scaron;eva,&nbsp; dok je ekspresija transkripcionih represora&nbsp; steroidogeneze&nbsp; (Arr19&nbsp; i&nbsp; Dax1)&nbsp; bila&nbsp; povećana specifično&nbsp; u&nbsp; istim&nbsp; ćelijama,&nbsp; ali&nbsp; ne&nbsp; i&nbsp; u&nbsp; ostatku&nbsp; testisa.<br />Transkripcioni&nbsp; profil&nbsp; markera&nbsp; mu&scaron;kog&nbsp; pola&nbsp; (<em>Sry,&nbsp; Sox9, Amh</em>)&nbsp; bio&nbsp; je&nbsp; izmenjen&nbsp; u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva.&nbsp; Transkripcija&nbsp; markera&nbsp; ženskog pola (<em>Rspo1, Wnt4</em>) u testisima,&nbsp; kao i ekspresija&nbsp; Cyp19a1 i&nbsp; produkcija estradiola (E2) u Leydig-ovim ćelijama,&nbsp; P21 i&nbsp; P80&nbsp;<em> Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva&nbsp; bile&nbsp; su&nbsp; povećane. Transkripcija&nbsp; markera&nbsp; mitohondrijalne&nbsp; biogenze (<em>Ppargc1a,&nbsp; Tfam</em>,&nbsp; <em>Mtnd1</em>)&nbsp; bila&nbsp; je&nbsp; smanjena&nbsp; u&nbsp; Leydigovim&nbsp; ćelijama&nbsp; P21&nbsp; <em>Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva,&nbsp; dok&nbsp; supromene&nbsp; ekspresije&nbsp; izostale&nbsp; u&nbsp; ovarijumima&nbsp; ženki&nbsp; istog&nbsp; genotipa.&nbsp; Isti&nbsp; markeri&nbsp; su&nbsp; bili&nbsp; povećani&nbsp; u&nbsp; nabdubrežnim&nbsp; žlezdama&nbsp; oba&nbsp; pola.&nbsp; Markeri&nbsp; mitohondrijalne fuzije/arhitekture&nbsp; (<em>Mfn1&nbsp; i&nbsp; Mfn2)</em>&nbsp; bili&nbsp; su&nbsp; povećani&nbsp; u Leydig-ovim ćelijama P21 <em>Insr/Igf1r</em>-DKO mi&scaron;eva, &scaron;to je&nbsp; praćeno&nbsp; i&nbsp; naru&scaron;enom&nbsp; mitohondrijalnom&nbsp; fazom steroidogeneze (produkcija progesterona), kao i brojem i&nbsp; morfologijom ovim organela.&nbsp; Ekspresija istih markera u ovarijumima&nbsp; bila&nbsp; je&nbsp; nepromenjena.&nbsp; Sumirano,&nbsp; rezultati ovog istraživanja&nbsp; su&nbsp; pokazali&nbsp; da su&nbsp; INSR i IGF1R&nbsp; važni za&nbsp; diferencijaciju&nbsp; i&nbsp; steroidogenu&nbsp; funkciju&nbsp; Leydig-ovih&nbsp; ćelija&nbsp; P21&nbsp; i&nbsp; P80&nbsp; mi&scaron;eva.&nbsp; Takođe,&nbsp; ovi&nbsp; receptori&nbsp; su&nbsp; važni regulatori&nbsp; markera&nbsp; mitohondrijalne&nbsp; biogeneze&nbsp; i fuzije/arhiteture u steroidogenim ćelijama mu&scaron;kih gonada&nbsp; P21 mi&scaron;eva, ali ne i u steroidogenim ćelijama ovarijuma.&nbsp;</p> / <p>Leydig cells of testes are the primary site of the male sex hormones&nbsp; synthesis.&nbsp; These&nbsp; hormones&nbsp; are&nbsp; indispensable for&nbsp; both&nbsp; reproductive&nbsp; and&nbsp; general&nbsp; health&nbsp; since&nbsp; serious health&nbsp; problems&nbsp; are&nbsp; often&nbsp; associated&nbsp; with&nbsp; their&nbsp; reduced production.&nbsp; Insulin&nbsp; and&nbsp; insulin-like&nbsp; growth&nbsp; factor&nbsp; 1, IGF1&nbsp; (insulin&nbsp; like&nbsp; growth&nbsp; factor&nbsp; 1),&nbsp; and&nbsp; signaling triggered through&nbsp; their receptors (INSR and IGF1R), are&nbsp; one of the key&nbsp; factors&nbsp; that regulate specific development of&nbsp; tissue&nbsp; including&nbsp; gonads.&nbsp; However,&nbsp; the&nbsp; role&nbsp; and mechanisms&nbsp; of&nbsp; these&nbsp; receptors&nbsp; action&nbsp; in&nbsp; steroidogenic tissues are not known enough. This study was designed to&nbsp; observe &nbsp; the role of INSR and IGF1R in regulating the differentiation and steroidogenic function of Leydig cells by using the model of prepubertal (P21) and adult (P80) male mice with the conditional deletion of the&nbsp; Insr&nbsp; and Igf1r&nbsp; genes&nbsp; in&nbsp; steroidogenic&nbsp; cells&nbsp; (<em>Insr/Igf1r-</em>DKO).&nbsp; In addition,&nbsp; male&nbsp; and&nbsp; female&nbsp; P21&nbsp; mice&nbsp; with&nbsp; the&nbsp; samedeletion were used to monitor the expression of the main markers&nbsp; of&nbsp; mitochondrial&nbsp; biogenesis&nbsp; and fusion/architecture&nbsp; in&nbsp; Leydig&nbsp; cells,&nbsp; ovaries&nbsp; and&nbsp; adrenal glands.&nbsp; The&nbsp; results&nbsp; confirmed&nbsp; that&nbsp; deletion&nbsp; of&nbsp;<em> Insr</em>&nbsp; and<em> Igf1r&nbsp;</em> in&nbsp; steroidogenic&nbsp; tissues&nbsp; influences&nbsp; differentiation and&nbsp; functional&nbsp; characteristics&nbsp; of&nbsp; Leydig&nbsp; cells&nbsp; isolated from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; mice,&nbsp; suggesting&nbsp; an&nbsp; appearance&nbsp; of &quot;feminization&quot;.&nbsp; The&nbsp; number&nbsp; of&nbsp; Leydig&nbsp; cells&nbsp; isolated from&nbsp; both&nbsp; P21&nbsp; and&nbsp; P80&nbsp; <em>Insr/Igf1</em>r-DKO&nbsp; mice&nbsp; was reduced.&nbsp; Morphology&nbsp; and&nbsp; ultrastructure&nbsp; of&nbsp; Leydig&nbsp; cells were&nbsp; disturbed&nbsp; in&nbsp; P21&nbsp; <em>Insr/Igf1r-</em>DKO&nbsp; mice. Steroidogenic capacity and activity, as well as expression of the main elements of&nbsp; steroidogenic machinery (<em>Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1&nbsp; and&nbsp; 6, Hsd17b3, Sf1) </em>were&nbsp; decreased&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from&nbsp; P21&nbsp; and&nbsp; P80 I<em>nsr/Igf1</em>r-DKO&nbsp; mice,&nbsp; while&nbsp; the&nbsp; expression&nbsp; of transcriptional&nbsp; repressors&nbsp; of&nbsp; steroidogenesis&nbsp; (<em>Arr19</em>&nbsp; and <em>Dax1) </em>was increased&nbsp; in the same cells, but not in the rest of&nbsp; the&nbsp; testes.&nbsp; Transcription&nbsp; profile&nbsp; of&nbsp; the&nbsp; male&nbsp; sex markers&nbsp; (<em>Sry,&nbsp; Sox9</em>,&nbsp; <em>Amh</em>)&nbsp; was&nbsp; altered&nbsp; in&nbsp; Leydig&nbsp; cells from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; <em>Insr/Igf1</em>r-DKO&nbsp; mice.&nbsp; Transcription of the female sex markers (<em>Rspo1, Wnt4</em>) in the testes, as well&nbsp; as&nbsp; <em>Cyp19a1&nbsp; </em>expression&nbsp; and&nbsp; estradiol&nbsp; (E2) production in Leydig cells,&nbsp; from P21 and P80&nbsp; I<em>nsr/Igf1</em>rDKO&nbsp; mice&nbsp; were&nbsp; increased.&nbsp; Transcription&nbsp; of mitochondrial&nbsp; biogenesis&nbsp; markers&nbsp; (<em>Ppargc1a,&nbsp; Tfam, Mtnd1</em>)&nbsp; was&nbsp; declined&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from&nbsp; P21<em> Insr/Igf1r-</em>DKO mice, while changes were absent in&nbsp; the ovaries of the same genotype.&nbsp; Transcription of the&nbsp; same markers&nbsp; was&nbsp; increased&nbsp; in&nbsp; the&nbsp; adrenal&nbsp; glands&nbsp; of&nbsp; both sexes.&nbsp; The&nbsp; mitochondrial&nbsp; fusion/architecture&nbsp; markers (<em>Mfn1</em>&nbsp; and&nbsp; <em>Mfn2</em>)&nbsp; were&nbsp; increased&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from<em> Insr/Igf1r</em>-DKO&nbsp; mice&nbsp; and&nbsp; followed&nbsp; by&nbsp; disturbedmitochondrial&nbsp; phase&nbsp; of&nbsp; steroidogenesis&nbsp; (progesterone production), as well as&nbsp; decreased&nbsp; number and&nbsp; disturbed morphology&nbsp; of&nbsp; mitochondria.&nbsp;&nbsp; Expression&nbsp; of&nbsp; the&nbsp; same markers&nbsp; in&nbsp; the&nbsp; ovaries&nbsp; was&nbsp; unchanged.&nbsp; In&nbsp; summary, results&nbsp; of&nbsp; this&nbsp; study&nbsp; showed&nbsp; that&nbsp; INSR&nbsp; and&nbsp; IGF1R&nbsp; are important in differentiation and steroidogenic function of Leydig&nbsp; cells&nbsp; from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; mice.&nbsp; Also,&nbsp; these receptors&nbsp; are&nbsp; important&nbsp; regulators&nbsp; of&nbsp; mitochondrial biogenesis&nbsp; and&nbsp;&nbsp; fusion/architecture&nbsp; markers&nbsp; in steroidogenic&nbsp; cells&nbsp; of&nbsp; P21&nbsp; male&nbsp; mice,&nbsp; but&nbsp; not&nbsp; in steroidogenic cells of ovaries.</p>

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