Uloga proupalnih i protuupalnih mehanizama u razvoju rezistencije posredovane ABC transporterima u upalnim bolestima crijeva

doctoral thesis

• Title (english): The role of proinflammatory and anti-inflammatory mechanisms in development of resistance mediated by ABC transporters in inflammatory bowel diseases
• Author: Ana Savić Mlakar
• Mentor: Ivna Svoboda-Beusan (mentor); MBZ: 45713
• Mentor: Krešo Bendelja (sumentor); MBZ: 229091
• Committee member: Nada Oršolić (član povjerenstva)
• Committee member: Branko Troskot (član povjerenstva); MBZ: 117465
• Committee member: Maja Matulić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2015, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

ABC transporteri sudjeluju u očuvanju crijevne barijere, te utječu na biodostupnost lijekova. Promjene njihove ekspresije mogu doprinijeti narušavanju barijere i razvoju upale, kao što je slučaj u upalnim bolestima crijeva. Njihova uloga u patogenezi upalnih bolesti crijeva nije u potpunosti razjašnjena. U ovom istraživanju odredili smo ekspresiju triju transportera: MDR1, MRP1 i BCRP, kod odraslih i djece oboljele od Crohnove bolesti (odrasli; n=25, djeca; n=26) i ulceroznog kolitisa (odrasli; n=27, djeca; n=20). Paralelno smo odredili i ekspresiju proupalnih citokina interferona (IFN)-γ, interleukina (IL)-2, IL-6, IL-1β i IL-17A, kao i njihove negativne regulatore, SOCS1 i SOCS3. Ispitanici su podijeljeni u četiri grupe: neliječeni bolesnici dijagnosticirani de novo, grupa bolesnika pod terapijom, te grupa u remisiji odnosno grupa zdrave kontrole (odrasli; n=10, djeca; n=15). Ovo istraživanje pokazuje izmijenjene ekspresije transportera koji koreliraju s povišenim ekspresijama citokina u oboljelih ispitanika. Nadalje, povišena ekspresija proupalnih citokina, popraćena povišenim ekspresijama njihovih negativnih regulatora, potvrđuju upalni proces kao dominantni patološki mehanizam u upalnim bolestima crijeva. Dakle, promjene ekspresija ABC transportera mogle bi imati funkcionalnu važnost u progresiji bolesti i liječenju.

Abstract (english)

Efflux transporters are crucial for the maintenance of gut homeostasis and influence drug bioavailability. Changes in their expression can disrupt the barrier which consequently results with inflammatory response, as observed in inflammatory bowel diseases (IBD). Their exact role in IBD pathogenesis is inconclusive. We have measured the expression of transporeters MDR1, MRP1 and BCRP in pediatric and adult patients with Crohn's disease (adults; n=25, pediatric; n=26) and ulcerative colitis (adults; n=27, pediatric; n=20). In paralell, we have assessed the expression of inflammatory cytokines IFN-γ , IL-2, IL-6, IL-1β and IL-17A, as well as their negative regulators, SOCS1 and SOCS3. Subjects were grouped as: newly diagnosed/untreated, active disease/treated, remission and controls (adults; n=10, pediatric; n=15). We showed that altered expression of efflux transporters correlated with cytokine expressions in IBD patients compared to controls. Furthermore, high cytokine expression, followed by high expression of their matched negative regulators, confirmed inflammatory process as the dominant pathological mechanism in IBD. In conclusion, alterations in ABC transporter expression could have functional importance in disease progression and treatment.

• Keywords: ABC transporteri; Crohnova bolest; Ulcerozni kolitis; citokini; supresori citokinske signalizacije
• Keywords (english): ABC transporters; Crohn's disease; Ulcerative colitis; cytokines; suppressors of cytokine signalling
• Language: croatian
• URN:NBN: urn:nbn:hr:217:827987
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-05-17 10:43:06