Uloga polimorfizama i ekspresije gena za hemokine CX3C ligand 1 i CXC ligand 16 i njihove receptore u nastanku i progresiji multiple skleroze u Srbiji
Roles of polymorphisms and expression of genes coding for chemokines CX3C ligand 1 and CXC ligand 16 and their receptors in the development and progression of multiple sclerosis in Serbia
Докторанд
Stojković, Ljiljana S.Ментор
Živković, MajaЧланови комисије
Savić-Pavićević, DušankaDinčić, Evica
Метаподаци
Приказ свих података о дисертацијиСажетак
Multipla skleroza je hroniĉna inflamatorna, autoimunska, demijelinizaciona i
neurodegenerativna bolest centralnog nervnog sistema (CNS-a). Hemokini i njihovi
receptori predstavljaju znaĉajne medijatore inflamacije koji uĉestvuju u patogenezi
odreĊenih hroniĉnih inflamatornih i autoimunskih bolesti meĊu kojima je i multipla
skleroza. Ciljni hemokini u ovoj studiji, CX3C ligand 1 (CX3CL1) i CXC ligand 16
(CXCL16), specifiĉni su po tome što postoje u dve forme - kao transmembranski
adhezivni molekuli i kao solubilni hemoatraktanti koji nastaju nakon proteolitiĉkog
seĉenja vanćelijskih hemokinskih domena njihovih transmembranskih formi. U toku
inflamatornog odgovora, na membrani endotelnih vaskularnih ćelija eksprimirani su
CX3CL1 i CXCL16, a na membrani leukocita receptori za CX3CL1 (CX3CR1) i
CXCL16 (CXCR6), te ovi hemokini i njihovi receptori posreduju u prodiranju leukocita
iz krvi u tkivo zahvaćeno inflamacijom, podsticanjem hemotaksije i adhezije leukocita
za aktivirani endotel krvno...g suda.
Ova studija obuhvata genetsko-epidemiološku analizu polimorfizama zamena
pojedinaĉnih nukleotida u kodirajućim regionima gena, koje rezultuju zamenama
aminokiselina. To su polimorfizmi V249I i T280M u genu za CX3CR1, i I123T i
A181V u genu za CXCL16. U prethodnim studijama je pokazano da ovi genski
polimorfizmi menjaju funkcionalna svojstva CX3CR1 i CXCL16, kao i da su asocirani
sa patogenezom odreĊenih hroniĉnih inflamatornih bolesti. Uzimajući to u obzir, ova
studija je imala za cilj da po prvi put ispita asocijaciju navedenih polimorfizama u
genima za CX3CR1 i CXCL16 sa nastankom i progresijom multiple skleroze.
Primenom alel-specifiĉne PCR metode i PIRA PCR-RFLP metode detektovani su
genotipovi polimorfizama V249I i T280M u genu za CX3CR1, kod zdravih kontrola i
pacijenata sa multiplom sklerozom. UtvrĊeno je da haplotip I249T280 u genu za CX3CR1
ima znaĉajno veću uĉestalost kod pacijenata sa relapsno-remitentnom (RR) formom, u odnosu na pacijente sa sekundarno-progresivnom (SP) formom multiple skleroze, što
znaĉi da ovaj haplotip ima protektivni efekat na progresiju RR u SP formu bolesti...
Multiple sclerosis is a chronic inflammatory, autoimmune, demyelinating and
neurodegenerative disease of the central nervous system (CNS). Chemokines and their
receptors are important mediators of inflammation, which are involved in pathogenesis
of certain chronic inflammatory and autoimmune diseases including multiple sclerosis.
Chemokines of interest in this study, CX3C ligand 1 (CX3CL1) and CXC ligand 16
(CXCL16), are specific in that they can exist either as transmembrane adhesion
molecules or soluble chemoattractants being generated by proteolytic cleavage of their
transmembrane forms’ extracellular domains. During the inflammatory response,
CX3CL1 and CXCL16 are expressed on the surface of vascular endothelium, while the
leukocytes produce membrane receptors for CX3CL1 (CX3CR1) and CXCL16
(CXCR6). Therefore, these chemokines and their receptors mediate the infiltration of
leukocytes from blood into the inflamed tissue areas, by stimulation of both chemotaxis
and adhesion of leuko...cytes to the activated endothelium of blood vessels.
This study is based on genetic epidemiological analysis of single nucleotide
polymorphisms, which are located in the coding regions of genes and result in amino
acids’ substitutions. These are V249I and T280M substitutions in the gene coding for
CX3CR1, and I123T and A181V substitutions in the gene coding for CXCL16. In
previous studies these polymorphisms have been associated with the functional
properties of CX3CR1 and CXCL16 as well as the pathogenesis of certain chronic
inflammatory diseases. Therefore, this study aimed to investigate the association of the
polymorphisms in CX3CR1 and CXCL16 genes with the development and progression
of multiple sclerosis. Using the allele-specific PCR and PIRA PCR-RFLP methods,
genotypes of CX3CR1 V249I and T280M polymorphisms were detected in healthy
controls and patients with multiple sclerosis. Following statistical analysis showed
significantly higher frequency of CX3CR1 I249T280 haplotype in patients with relapsingremitting
(RR) form, compared to patients with secondary-progressive (SP) form of multiple sclerosis, so this haplotype had a protective effect on progression of RR to SP
form of the disease...
Факултет:
Универзитет у Београду, Биолошки факултетДатум одбране:
20-09-2013Пројекти:
- Интегрална студија идентификације регионалних генетских фактора ризика и фактора ризика животне средине за масовне незаразне болести хумане популације у Србији - INGEMA_S (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41028)
- Генетска основа хуманих васкуларних и инфламаторних болести (RS-MESTD-Basic Research (BR or ON)-175085)