{"id":5962,"date":"2026-10-19T09:48:14","date_gmt":"2026-10-19T09:48:14","guid":{"rendered":"https:\/\/phd.hi.is\/doktorsvorn\/doktorsvorn-i-lif-og-laeknavisindum-amaranta-u-armesto-jimenez\/"},"modified":"2026-10-19T09:48:14","modified_gmt":"2026-10-19T09:48:14","slug":"doktorsvorn-i-lif-og-laeknavisindum-amaranta-u-armesto-jimenez","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-lif-og-laeknavisindum-amaranta-u-armesto-jimenez\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed l\u00edf- og l\u00e6knav\u00edsindum – Amaranta \u00da. Armesto Jimenez"},"content":{"rendered":"
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F\u00f6studaginn 17 \u00e1g\u00fast ver Amaranta \u00da. Armesto Jimenez doktorsritger\u00f0 s\u00edna \u00ed\u00a0 l\u00edf- og l\u00e6knav\u00edsindum vi\u00f0 H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: Hlutverk erf\u00f0abreytileika \u00ed stj\u00f3rnsv\u00e6\u00f0i MUC5B gensins og \u00e1hrif hans \u00e1 lungnatrefjun.<\/p>\n

Dissecting the regulatory role for a MUC5B polymorphism involved in Idiopathic Pulmonary Fibrosis.<\/p>\n

Andm\u00e6lendur eru dr. Gisli Jenkins, pr\u00f3fessor vi\u00f0 University of Nottingham, Englandi, og dr. Gu\u00f0mundur Hrafn Gu\u00f0mundsson, pr\u00f3fessor vi\u00f0 H\u00e1sk\u00f3la \u00cdslands.<\/p>\n

Umsj\u00f3narkennari og lei\u00f0beinandi var Magn\u00fas Karl Magn\u00fasson, pr\u00f3fessor vi\u00f0 L\u00e6knadeild H\u00e1sk\u00f3la \u00cdslands. Auk hans s\u00e1tu \u00ed doktorsnefnd dr. Eir\u00edkur Steingr\u00edmsson pr\u00f3fessor, dr. Gunnar Gu\u00f0mundsson pr\u00f3fessor, dr. Erna Magn\u00fasd\u00f3ttir d\u00f3sent og dr. \u00de\u00f3rarinn Gu\u00f0j\u00f3nsson pr\u00f3fessor, \u00f6ll vi\u00f0 L\u00e6knadeild.<\/p>\n

Dr. Engilbert Sigur\u00f0sson, pr\u00f3fessor og deildarforseti L\u00e6knadeildar, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed \u00d6skju, stofu 132, og hefst kl. 13:00.<\/p>\n

\u00c1grip af ranns\u00f3kn <\/strong><\/p>\n

Lungnatrefjun af \u00f3\u00feekktum uppruna (IPF) er alvarlegur og \u00f3l\u00e6knandi sj\u00fakd\u00f3mur. Lifun eftir greiningu er um 3-5 \u00e1r og eina l\u00e6knandi me\u00f0fer\u00f0in er lungna\u00edgr\u00e6\u00f0sla, sem ekki allir \u00feola. N\u00fdveri\u00f0 hafa komi\u00f0 fram lyf \u00e1 bor\u00f0 vi\u00f0 pirferidone og nintedanib sem hafa n\u00e1\u00f0 a\u00f0 h\u00e6gja \u00e1 framgangi sj\u00fakd\u00f3msins me\u00f0 \u00fev\u00ed a\u00f0 hamla bo\u00f0ferla sem lei\u00f0a til trefjunar. \u00de\u00f3 er \u00fea\u00f0 \u00feannig a\u00f0 IPF greinist oftast seint \u00ed sj\u00fakd\u00f3msferlinu \u00feannig a\u00f0 l\u00edkur \u00e1 l\u00e6knandi me\u00f0fer\u00f0 eru minni. \u00dev\u00ed er afar mikilv\u00e6gt a\u00f0 uppg\u00f6tva n\u00fdja \u00e1h\u00e6ttu\u00fe\u00e6tti sj\u00fakd\u00f3msins sem h\u00e6gt er a\u00f0 nota til greiningar fyrr \u00ed ferlinu. N\u00fdleg erf\u00f0amengis\u2013tengslagreining \u00e1 IPF sj\u00faklingum samanbori\u00f0 vi\u00f0 heilbrig\u00f0a einstaklinga leiddi \u00ed lj\u00f3s a\u00f0 einbasabreytileiki (G-T) (rs35705950) \u00ed st\u00fdrisv\u00e6\u00f0i MUC5B gensins var til sta\u00f0ar \u00ed 45% IPF sj\u00faklinga samanbori\u00f0 vi\u00f0 11% heilbrig\u00f0ra. \u00deessi breytileiki er \u00ed dag st\u00e6rsti \u00feekkti \u00e1h\u00e6ttu\u00fe\u00e1ttur fyrir IPF. G-T breytingin hefur einnig veri\u00f0 tengd vi\u00f0 snemmkomna trefjun \u00ed lungum, sem bendir til tengsla st\u00f6kkbreytinga \u00ed MUC5B og lungnatrefjunar. Fram til \u00feessa hefur ekki veri\u00f0 lj\u00f3st hvernig \u00feessi einbasabreytileiki hefur \u00feessi \u00e1hrif. \u00cd \u00feessu verkefni eru sameindal\u00edffr\u00e6\u00f0ilegar aflei\u00f0ingar st\u00f6kkbreytingarinnar \u00e1 tj\u00e1ningarstj\u00f3rn MUC5B \u00ed \u00feekjufrumum lungna \u00fatsk\u00fdr\u00f0ar, en me\u00f0al annars er notast vi\u00f0 CRISPR-Cas9 erf\u00f0abreytingara\u00f0fer\u00f0ina. Ni\u00f0urst\u00f6\u00f0ur ranns\u00f3knarinnar s\u00fdna fram \u00e1 aukna tj\u00e1ningu \u00ed vi\u00f0urvist T-einbasabreytileikans. \u00deessi tj\u00e1ningaraukning vir\u00f0ist drifin af tveimur atbur\u00f0um; CpG metyleringar-eyja ey\u00f0ileggst (sem \u00e1\u00f0ur hefur veri\u00f0 tengd vi\u00f0 b\u00e6lingu \u00e1 tj\u00e1ningu) og n\u00fdr bindista\u00f0ur myndast fyrir hvetjandi umritunar\u00fe\u00e1ttinn C\/EBP\u03b2. Ennfremur s\u00fdnum vi\u00f0 g\u00f6gn sem tengja T-erf\u00f0abreytileika MUC5B vi\u00f0 lykil\u00fe\u00e6tti frumu\u00e1lags, svo sem minnka\u00f0a frumufj\u00f6lgun, aukna tj\u00e1ningu \u00e1 umritunar\u00fe\u00e6ttinum C\/EBP\u03b6 og aukinn fj\u00f6lda hvatbera. \u00deetta verkefni hefur varpa\u00f0 n\u00fdju lj\u00f3si \u00e1 rs35705950 st\u00f6kkbreytinguna \u00ed IPF og tengt oftj\u00e1ningu \u00e1 MUC5B vi\u00f0 sj\u00fakd\u00f3minn me\u00f0 beinum h\u00e6tti. \u00deessar ni\u00f0urst\u00f6\u00f0ur tengja MUC5B beint vi\u00f0 IPF og leggja grunn a\u00f0 n\u00fdrri s\u00fdn \u00e1 \u00fev\u00ed hvernig \u00feessi einbasabreytileiki tengist tilur\u00f0 IPF.<\/p>\n

Lykilor\u00f0: CEBPB, lungnatrefjun, metylering, MUC5B rs35705950, st\u00f6kkbreytingar.<\/p>\n

Abstract<\/strong><\/p>\n

Idiopathic pulmonary fibrosis is a severe lung disease with unknown aetiology. The lifespan is approximately 3 to 5 years after diagnosis, and the treatments available such as lung transplant are high risk and are not suitable for all patients. In recent years, new drugs such as pirferidone and nintedanib have proved to slow down IPF progression by targeting profibrotic signaling pathways. However, IPF is usually detected in advanced stages, diminishing the beneficial effect of new treatments. Therefore, to find novel risk factors and preclinical characteristics of IPF has become an important task in the field. A recent genome wide association study (GWAS) performed in IPF patients compared to controls revealed a common MUC5B cis-regulatory region polymorphism (rs35705950), where a G is replaced by a T allele in around 45% of IPF patient compared to an 11% allele frequency in controls. This polymorphism has become the strongest risk factor (genetic and otherwise) associated with IPF. Furthermore, the presence of the minor T allele has been associated to subclinical lung fibrosis, suggesting an important role of the MUC5B polymorphism early in IPF development. However, the mechanism underlying the effect of the MUC5B cis-regulatory polymorphism remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression in human bronchial epithelial cells. The results shown in this project corroborate the gain of function role of the minor T allele. Also, we have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. On the one hand, the minor T allele destroys a CpG methylation site, previously associated with MUC5B inhibition. On the other hand, the replacement of the wild type G allele with a T allele generates a novel C\/EBP\u03b2 activating transcription binding site. Using two different approach models that include the use of luciferase reporter vectors and CRISPR-Cas9 editing technique we show the differential methylation pattern between both alleles and analyze the effect on MUC5B expression. Also, based on CRISPR edited cell lines we show the binding of C\/EBP\u03b2 in MUC5B cis regulatory domain only in presence of the minor T allele. Finally, we show preliminary data that correlates the MUC5B overexpression in T allele cells to characteristics of the cellular stress, as reduced proliferation ratio, overexpression of the ER stress marker C\/EBP\u03b6 transcription factor and increased number of mitochondria. Altogether, the findings presented in this project assessed the bases for a better understanding of the rs35705950 T allele effect in MUC5B overexpression that would lead to specific treatments in the future as well as validate the use of rs35705950 polymorphism as a risk marker for IPF development.<\/p>\n

Keywords: CEBPB, Idiopathic pulmonary fibrosis, methylation, MUC5B, rs35705950 polymorphism.<\/p>\n

Um doktorsefni\u00f0 \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 <\/strong><\/p>\n

Amaranta \u00darsula Armesto Jim\u00e9nez er f\u00e6dd \u00ed \u00e1g\u00fast 1989, \u00ed Marchena, Sevilla \u00e1 Sp\u00e1ni. H\u00fan h\u00f3f n\u00e1m vi\u00f0 Deild tilraunav\u00edsinda vi\u00f0 Pablo de Olavidade University (UPO) \u00ed Sevilla og lauk BSc-gr\u00e1\u00f0u \u00ed l\u00edft\u00e6kni 2012. \u00c1ri s\u00ed\u00f0ar, 2013, lauk h\u00fan meistaragr\u00e1\u00f0u \u00ed \u00fe\u00fd\u00f0ingarranns\u00f3knum \u00ed l\u00edfeindafr\u00e6\u00f0i vi\u00f0 H\u00e1sk\u00f3lann \u00ed Cordoba. Amaranta h\u00f3f doktorsn\u00e1m vi\u00f0 H\u00e1sk\u00f3la \u00cdslands 2014 og hefur unni\u00f0 a\u00f0 doktorsverkefni s\u00ednu vi\u00f0 L\u00edfv\u00edsindasetur.<\/p>\n<\/div><\/div>","protected":false},"featured_media":1113,"template":"","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"_phd_date_start":"2018-08-17T13:00:00+00:00","_phd_date_end":"2018-08-17T16:00:00+00:00","_phd_location":"Askja Stofa N-132","_phd_admission":"A\u00f0gangur \u00f3keypis","_phd_thesis_title":"Hlutverk erf\u00f0abreytileika \u00ed stj\u00f3rnsv\u00e6\u00f0i MUC5B gensins og \u00e1hrif hans \u00e1 lungnatrefjun","_phd_source_url":"https:\/\/gamli.hi.is\/vidburdir\/doktorsvorn_i_lif_og_laeknavisindum_amaranta_u_armesto_jimenez","_phd_source_node_id":"311711","_phd_source_type":"vidburdir","_phd_member_id":116,"footnotes":""},"phd_school":[60,67],"phd_discipline":[70],"class_list":["post-5962","phd_defence","type-phd_defence","status-publish","has-post-thumbnail","hentry","phd_school-heilbrigdisvisindasvid","phd_school-laeknadeild","phd_discipline-phd-i-lif-og-laeknavisindum"],"_links":{"self":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence\/5962","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence"}],"about":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/types\/phd_defence"}],"version-history":[{"count":0,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence\/5962\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/media\/1113"}],"wp:attachment":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/media?parent=5962"}],"wp:term":[{"taxonomy":"phd_school","embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_school?post=5962"},{"taxonomy":"phd_discipline","embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_discipline?post=5962"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}