magistrsko delo
Suzana Stokić (Author), Uroš Potočnik (Mentor), Katja Repnik (Co-mentor)

Abstract

Multipla skleroza (MS) je najbolj pogosta kronična avtoimuna bolezen centralnega živčnega sistema. Epidemiološki podatki kažejo, da tako genetski kot tudi okoljski dejavniki prispevajo k tveganju za razvoj MS. Zdravljenje se navadno začne z biološkimi zdravili interferoni beta (INF-beta) in glatiramer acetat (GA). Iz literature je razvidno, da 30-50 % bolnikov ne odgovarja na terapijo prvega reda, na kar vplivajo tudi razlike v genetski variabilnosti med posamezniki. Zato je zelo pomembno identificirati biooznačevalce, s katerimi bi lahko napovedali odziv na terapijo še pred zdravljenjem ter s tem zmanjšali stranske učinke in dosegli maksimalno učinkovitost in varnost v zgodnji fazi bolezni. V tem magistrskem delu smo želeli s pomočjo spletnih podatkovnih zbirk ter z ustreznimi bioinformatskimi orodji in orodji genske ontologije raziskati farmakogenomiko MS, na podlagi pridobljenih podatkov predpostaviti molekularno biološko pot odziva na farmakološko zdravljenje ter poiskati skupne biološke mehanizme, ki napovedujejo najboljši odziv na zdravljenje MS. Pri zdravljenju z INF-beta so se pokazale kot pomembne biološke poti signalna pot interferona tipa 1, celični odgovor na interferon tipa 1 ter odgovor na interferon tipa 1, kar je smiselno glede na samo zdravilo, vendar smo opazili, da te poti vključujejo le malo genov, ki bi lahko sodelovali pri odzivu. Pri zdravljenju z GA pa so ključne biološke poti imunski odziv, proces imunskega sistema ter citokine signalne poti. Gene povezane z odzivom na zdravljenje smo povezali v mrežo, s katero smo dobili vpogled v proteinsko povezavo med posameznimi geni. Iz mrež je razvidno veliko več povezav kot smo pričakovali, kar pomeni, da imajo proteini več interakcij sami med seboj kot bi to pričakovali od naključnega seta. Poleg tega so geni, povezani z odzivom na zdravljene z določenim biološkim zdravilom, prav tako vključeni še v druge biološke poti povezane s sami imunskim sistemom in njegovo kompleksnostjo.

Keywords

multipla skleroza;zdravljenje MS;biološka zdravila;INF-beta;GA;humana monoklona protitelesa;genska ontologija;GWA študije;magistrske naloge;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher: [S. Stokić]
UDC: 575.111(043.2)
COBISS: 22600214 Link will open in a new window
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Downloads: 76
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Other data

Secondary language: English
Secondary title: Analyis of biological pathway s with response to biological therapy in patients with multiple sclerosis using tolls of gene ontology
Secondary abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Epidemiologic data show that environmental and genetic factors play a key role in the development of MS. Current MS treatments include immunomodulatory and immunosuppressive drugs and monoclonal antibodies. The most frequently used therapies are interferon- beta (INF-beta) and glatiramer acetate (GA). The response to therapy differs among individuals and around 30-50 % patients doesn't respond. Although the reason is yet unknown many studies showed the role of genetics in treatment response. It is important to find biomarkers to identify likely responders and/or those who may have treatment-limiting adverse reactions. In this work we focused on pharmacogenomic studies with INF-beta and GA in RRMS patients. In analysis we included studies that were investigating associations between genetic variation and treatment response. In next phases with use of bioinformatics tools and gene ontology we tried to find biological mechanisms which predict response to pharmacological treatment of MS. With use of interaction networks we tried to demonstrate interaction between the proposed genes. Our research showed the most significant biological processes in INF-beta treatment are type I interferon signaling pathway, cellular response to type I interferon, response to type I interferon. In GA treatment the most significant biological processes are immune response, immune system process, cytokine-mediated signaling pathway. Interaction networks showed more interactions among chosen genes than what would be expected for a random set of proteins of similar size, drawn from the genome. Such an enrichment indicates that the proteins are at least partially biologically connected, as a group. And also that many genes that indicate response to treatment are involved also in other biological pathways in complex immune system.
Secondary keywords: multiple sclerosis;MS treatment;biologicals;INF-beta;GA;humanized monoclonal antibodies;gene ontology;GWAS;
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Pages: VIII, 55 str.
ID: 11200931