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Title:VLOGA RECEPTORJEV ENDOKANABINOIDNEGA SISTEMA CB1 IN CB2 PRI INHIBICIJI CITOKINA TNF-e1 V MONONUKLEARNIH LIMFOIDNIH CELICAH BOLNIKOV S CROHNOVO BOLEZNIJO
Authors:ID Hribar, Žan (Author)
ID Potočnik, Uroš (Mentor) More about this mentor... New window
ID Deželak, Matjaž (Comentor)
Files:.pdf UN_Hribar_Zan_2016.pdf (2,76 MB)
MD5: 19A59946014F40A4202E52EAA6C89751
 
Language:Slovenian
Work type:Bachelor thesis/paper
Typology:2.11 - Undergraduate Thesis
Organization:FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:Kronično vnetna črevesna bolezen (KVČB) je avtoimunska kompleksna bolezen, ki lahko prizadene celoten prebavni trakt pri človeku. Pojavlja se v obliki Crohnove bolezni (CD), ulceroznega kolitisa (UC) ter intermedialnega kolitisa (IK). Sama patogeneza bolezni še ni povsem pojasnjena, so pa različne študije že identificirale kar nekaj potencialnih genov, ki bi lahko sodelovali pri tej bolezni. Velik problem te bolezni se kaže predvsem v tem, da še ni zdravila, ki bi absolutno odpravilo vzroke bolezni, pa tudi simptomatsko zdravljenje je pogosto neučinkovito, z mnogimi stranskimi učinki. Zadnje čase je za zdravljenje KVČB v uporabi humanizirano monoklonsko protitelo adalimumab (ADA), ki specifično in z visoko afiniteto veže dejavnik tumorske nekroze-α (TNF). TNF je osrednji citokin vnetnega in imunskega odziva, torej ADA deluje protivnetno in zmanjšuje imunski odziv telesa. Vendar je već kliničnih študij pokazalo, da je zdravljenje z ADA uspešno le pri približno dveh tretjinah bolnikov. O genetskih in biokemijskih razlogih za neodziv na zdravljenje z ADA je znanega zelo malo, se pa v tem pogledu zdi endokanabinoidni sistem (EKS) kot zelo verjeten vzročni dejavnik, saj je njegovo sodelovanje pri vnetnih in imunskih procesih dobro poznano. Glavna cilja naše raziskave sta bila proučiti povezanost polimorfizmov enega nukleotida (SNP) ter gensko ekspresijo endokanabinoidnih receptorjev (CB) 1 in 2, na eni strani z dovzetnostjo za posamezen podtip KVČB, in na drugi strani z odzivom bolnikov s CD na zdravljenje z ADA. V ta namen smo v mononuklearnih celicah periferne krvi iz 276 zdravih posameznikov, 61 bolnikov z ulcerativnim kolitisom, 113 bolnikov s Crohnovo boleznijo na standardni terapiji (CB) in iz 119 bolnikov s Crohnovo boleznijo, zdravljenih z ADA genotipizirali 6 SNP v CNR1 in CNR2 ter izmerili njuno gensko ekspresijo. Na osnovi rezultatov smo naredili dva tipa asociacijskih analiz, ti. "case-control" in farmakogenomsko asociacijsko študijo. Za potrditev ekspresije CNR1 in CNR2 na proteinskem nivoju smo v vzorcih najbolj očitnih odzivnikov in neodzivnikov na zdravljenje z ADA izvedli analizo s prenosom western. "Case-control" študija je pokazala signifikantne razlike v frekvencah genotipov med kontrolami in posameznimi kohortomi bolnikov. Genotipa CT in TT rs4237 (PITHD1) sta bila povezana z večjo dovzetnostjo za razvoj hujših oblik CD, katere je potrebno zdraviti z biološkimi zdravili, medtem ko je bil genotip CC rs13197090 (RARS2) povezan z večjo dovzetnostjo za pojav oblik CD in UC, za zdravljenje katerih zadostuje klasična terapija. Starost ob diagnozi ni bila povezano z nobeno od genskih ekspresij CNR1 in CNR2, sta pa obe bili v signifikantni medsebojni korelaciji v vseh kohortah, z izjemo bolnikov z UC. Farmakogenomska študija je pokazala signifikantne razlike med frekvencami alelov in genotipov odzivnikov in neodzivnikov v 4. tednu zdravljenja z ADA. Bolniki z genotipom GG rs1049353 (CNR1) oz. genotipoma CCTT in TTTT rs35761398 (CNR2) so se v večjem deležu odzvali na zdravljenje z ADA. V 30. tednu zdravljenja je bila genska ekspresija CNR2 signifikantno nižja pri odzivnikih na zdravljenje z ADA v primerjavi z neodzivniki.
Keywords:kronična vnetna črevesna bolezen, Crohnova bolezen, kanabinoidi, adalimumab, genotipizacija, genska ekspresija, asociacijska analiza
Place of publishing:Maribor
Publisher:[Ž. Hribar]
Year of publishing:2016
PID:20.500.12556/DKUM-62859 New window
UDC:615.34-002(043.2)
COBISS.SI-ID:20299798 New window
NUK URN:URN:SI:UM:DK:8IDJB0RG
Publication date in DKUM:16.09.2016
Views:1876
Downloads:163
Metadata:XML DC-XML DC-RDF
Categories:KTFMB - FKKT
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Secondary language

Language:English
Title:THE INVOLVEMENT OF ENDOCANNABINOID RECEPTORS CB1 AND CB2 IN INHIBITION OF TNF-e1 CYTOKINE IN MONONUCLEAR LYMPHOID CELLS FROM CROHN'S DISEASE PATIENTS
Abstract:Chronic inflammatory bowel disease (IBD) is an auto-immune complex disease, which may affect the entire gastrointestinal tract in humans. It manifests in the form of Crohn's disease (CD), ulcerative colitis (UC) and the intermediary colitis (IC). The pathogenesis of the disease is not yet completely explained, but various studies have already identified a number of potential genes that could be involved in the disease. A major problem of the disease is primarily in the fact that there is no treatment that would absolutely eliminate the causes of the disease, as well as the symptomatic treatment is often ineffective, with many side effects. Lately, the treatment of IBD in the use of a humanized monoclonal antibody, adalimumab (ADA), which specifically and with high affinity ties to the tumor necrosis factor-α (TNF). TNF is a key cytokine of the inflammatory and immune response. ADA has anti-inflammatory propreties and reduces the immune response of the body. However, several clinical studies have shown that treatment with ADA is successful in only about two thirds of patients. There is very little known about the genetic and biochemical reasons for the failure to respond to treatment with ADA, but in this aspect the endocannabinoid system (EKS) seems a very likely causal factor, because of its involvement in inflammatory and immune processes, which are well known. The main objective of our study was to examine the relationship of polymorphisms of one nucleotide (SNP) and the genetic expression of endocannabinoid receptors (CB) 1 and 2, on the one hand with susceptibility to a particular subtype of IBD , and on the other hand, the response of patients with CD to treatment with ADA . For this purpose we took the peripheral mononuclear blood cells from 276 healthy individuals and 61 patients with ulcerative colitis, 113 patients with Crohn's disease in the standard therapy ( CB ) and from 119 patients with Crohn's disease treated with ADA and genotyped 6 SNPs in CNR1 and CNR2 and measured their gene expression. Based on the results, we have made two types of association analyzes, a so-called "case - control" and pharmacogenomic associative study. To confirm the expression of CNR1 and CNR2 on the protein level, in the samples which were the most obvious responders and nonresponders to treatment with ADA, we used western blot technique. "Case - control " study showed significant differences in the genotype frequencies between controls and individual cohorts of patiens. Genotypes CT and TT rs4237 ( PITHD1 ) were associated with increased susceptibility to develop more severe forms of the CD , which should be treated with biological drugs , while the genotype CC rs13197090 ( RARS2 ) is associated with increased susceptibility for developing forms of CD and UC , for treatment which is sufficient to conventional therapy . Age at diagnosis was not associated with any of CNR1 and CNR2 gene expression, but both were any significant correlation in all cohorts, with the exception of patients with UC . Pharmacogenomic study showed no significant difference between the frequencies of alleles and genotypes of responders and nonresponders in the fourth week of treatment with ADA. Patients with genotype of GG rs1049353 (CNR1) respectively. Genotypes CCTT and TTTT rs35761398 (CNR2) have a larger proportion of responders to treatment with ADA . At at the 30th week of treatment CNR2 expression was significantly lower in the responders to treatment with ADA compared to nonresponders
Keywords:inflammatory bowel disease, Crohn's disease, cannabinoids, adalimumab, genotyping, gene expression, association analysis


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