Primjena genomske analize u istraživanju biomarkera razvoja multiple skleroze u bolesnika s optičkim neuritisom

Habek, Mario (2010) Primjena genomske analize u istraživanju biomarkera razvoja multiple skleroze u bolesnika s optičkim neuritisom. PhD thesis, Sveučilište u Zagrebu.

Preview

PDF Download (2MB) | Preview

Abstract

Introduction: Development of gene markers which are able to determin risk for development of MS after optic neuritis, would be of particular importance in early diagnosis and therapeutic intervention in patients with multiple sclerosis. Therfore, our hypothesis was that gene microarray analysis of whole blood samples in patients with acute optic neuritis will determine differentially expressed genes which can serve as potential gene markers for diagnosis and follow-up of multiple sclerosis. ----- Materials and methods: We included 15 patients with acute optic neuritis and 10 healthy controls. Gene expression was analyzed with DNA microarrays for whole human genome analysis (Human Genome U133 PLUS 2.0 GeneChip, Affymetrix) which contains 54 675 25-base pairs. Results of 9 selected genes were confirmed with PCR. Aditional analysis was performed with gene ontology analysis and GSEA. ----- Results: This is the first study of whole genome expression analysis of whole blood in patients with optic neuritis. Totally 722 genes with different expression were identified , 377 with increased expression and 345 with decreased expression profiles. Based on statistical significance and up to know known involvement in MS, from 722 genes, 9 were selected as potential biomarkers, 5 with increased expression (PTPRC, SLC11A1, SLPI, NAIP, LPXN) and 4 with decreased expression (CCR3, ITGA4, CD28, SLAMF7). Gene ontology analysis and GSEA showed that protein phosphorilation and intracelular compartment, apoptosis inhibition, and pathways involved in cell cycles, T- and B-cell functions and anti-inflammatory CNS pathways are implicated in MS pathology. ----- Conclusion: Gene expression analysis of whole blood showed significant differences in expression profiles of patients with optic neuritis compared with healthy control. As well, pathways involved in T-cell regulation and anti-inflammatory pathways within CNS are identified as important in early phases of MS.

Abstract in Croatian

Uvod: Otkrivanje genskih markera koji mogu predvidjeti razvoj multiple skleroze nakon optičkog neuritisa imalo bi veliku korist u dijagnostičkoj, ali i ranoj terapijskoj intervenciji u bolesnika s multiplom sklerozom. Genskom analizom ekspresijskog profila pune krvi u pacijenata s optičkim neuritisom, klinički izoliranim sindromom, moguće je odrediti diferencijalno eksprimirane gene koji mogu poslužiti kao potencijalni genski markeri za dijagnosticiranje i praćenje razvoja multiple skleroze. ----- Materijali i metode: U istraživanje je uključeno 15 bolesnika s akutnim optičkim neuritisom i 10 zdravih kontrola. Genska ekspresija analizirana je uporabom DNA čipa za analizu cjelokupnog humanog genoma (Human Genome U133 PLUS 2.0 GeneChip, Affymetrix) koji sadrži 54 675 25-baznih proba. Rezultati odabranih 9 gena potvrđeni su PCR-om. Dodatnu su rezultato obrađeni analizom genske ontologije i GSEA. ----- Rezultati: Ovo je prvo istraživanje ukupne genske ekspresije u krvi bolesnika s optičkim neuritisom. Ukupno je nađeno 722 promijenjena gena, od kojih je 377 pokazalo povišenu razinu ekspresije, a 345 smanjenu razinu ekspresije. Od ukupno 722 promijenjeno gena, prema statističkoj značajnosti i dosad poznatoj ulozi u multiploj sklerozi, njih 9 izabrano je za potencijalne biomarkere; 5 sa povišenom razinom ekspresije (PTPRC, SLC11A1, SLPI, NAIP, LPXN) te 4 gena sa sniženom razinom ekspresije (CCR3, ITGA4, CD28, SLAMF7). Analizom genske ontologije i GSEA je pokazana važnost proteinske fosforilacije i unutarstaničnog odjeljka, inhibicja apoptoze, gena vezanih uz stanični ciklus te genskih puteva vezanih uz funkciju B i T stanica, kao i interleukina vezanih uz protuupalne procese. ----- Zaključak: Analizom genske ekspresije pune krvi pokazane su značajne razlike u ekspresijskom profilu bolesnika s optičkim neuritisom u usporedbi sa zdravim kontrolama. Također su identificirani putevi vezani uz T staničnu regulaciju i protu-upalno djelovanje kao važne čimbenike u ranoj fazi multiple skleroze.

Actions (login required)

View Item

Downloads