{"id":5963,"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-andrea-garcia-llorca\/"},"modified":"2026-10-19T09:48:14","modified_gmt":"2026-10-19T09:48:14","slug":"doktorsvorn-i-lif-og-laeknavisindum-andrea-garcia-llorca","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-lif-og-laeknavisindum-andrea-garcia-llorca\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed l\u00edf- og l\u00e6knav\u00edsindum – Andrea Garc\u00eda-Llorca"},"content":{"rendered":"
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\u00deri\u00f0judaginn 18. febr\u00faar ver Andrea Garc\u00eda-Llorca doktorsritger\u00f0 s\u00edna \u00ed l\u00edf- og l\u00e6knav\u00edsindum vi\u00f0 L\u00e6knadeild H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: Umritunar\u00fe\u00e1tturinn microphthalmia-associated transcription factor (Mitf) og hlutverk hans \u00ed starfsemi augna m\u00fasa. The role of the microphthalmia-associated transcription factor (Mitf) in mouse eye function<\/strong>.<\/p>\n

Andm\u00e6lendur eru dr. Kai Kaarniranta, pr\u00f3fessor vi\u00f0 H\u00e1sk\u00f3lann \u00ed Kuopio, Finnlandi og dr. Hans T\u00f3mas Bj\u00f6rnsson, pr\u00f3fessor vi\u00f0 L\u00e6knadeild H\u00e1sk\u00f3la \u00cdslands.\u00a0<\/p>\n

Umsj\u00f3narkennari var dr. \u00de\u00f3r Eysteinsson og me\u00f0lei\u00f0beinandi var dr. Margr\u00e9t Helga \u00d6gmundsd\u00f3ttir. Auk \u00feeirra s\u00e1tu \u00ed doktorsnefnd dr. Eir\u00edkur Steingr\u00edmsson, pr\u00f3fessor, dr. J\u00f3na Freysd\u00f3ttir, pr\u00f3fessor og dr. \u00de\u00f3rarinn Gu\u00f0j\u00f3nsson, pr\u00f3fessor.<\/p>\n

Engilbert Sigur\u00f0sson, pr\u00f3fessor og forseti L\u00e6knadeildar H\u00e1sk\u00f3la \u00cdslands, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed H\u00e1t\u00ed\u00f0asal H\u00e1sk\u00f3la \u00cdslands og hefst kl. 13.00.<\/p>\n

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

Umritunar\u00fe\u00e1tturinn microphthalmia-associated transcription factor (Mitf) er mikilv\u00e6gur fyrir e\u00f0lilega \u00feroskun og starfsemi lit\u00feekju (retinal pigment epithelium, RPE) augans og lj\u00f3snema \u00ed m\u00fasum. St\u00f6kkbreytingar \u00ed geni \u00feessu sem sker\u00f0a starfsemi \u00feess geta valdi\u00f0 minnkun litmyndunar \u00ed augum, van\u00feroskun augnanna (microphthalmiu) og blindu. Sj\u00e1lfs\u00e1t (autophagy) er mikilv\u00e6gt hreinsunarferli \u00ed frumum sem vi\u00f0heldur samv\u00e6gi (homeostasis) \u00ed lit\u00feekju. \u00d3e\u00f0lilegt e\u00f0a skert sj\u00e1lfs\u00e1t er \u00fe\u00e1ttur \u00ed aldursh\u00e1\u00f0ri hr\u00f6rnun mi\u00f0gr\u00f3far (AMD) \u00ed m\u00f6nnum. Markmi\u00f0 \u00feessarar ranns\u00f3knar var a\u00f0 greina \u00e1hrif tiltekinna st\u00f6kkbreytinga \u00ed Mitf geninu \u00e1 byggingu og starfsemi sj\u00f3nhimnu og lit\u00feekju augans, og athuga hvort Mitf st\u00fdrir sj\u00e1lfs\u00e1ti \u00ed lit\u00feekjufrumum \u00ed m\u00fasum. Eftirfarandi st\u00f6kkbreytingar voru sko\u00f0a\u00f0ar \u00ed \u00feessari ranns\u00f3kn: Mitfmi-vga9\/+, Mitfmi-enu22(398)\/Mitfmi-enu22(398), MitfMi-Wh\/+, MitfMi-Wh\/Mitfmi, MitfK243R;Tyr::Cre og m\u00fds af villiger\u00f0 (C5BL\/6J) sem vi\u00f0mi\u00f0. Minnku\u00f0 litmyndun var greinileg \u00ed augnbotnum allra st\u00f6kkbreyttu d\u00fdranna. Fullvaxta Mitfmi-vga9\/+ and Mitfmi-enu22(398)\/Mitfmi-enu22(398) \u00a0m\u00fds eru me\u00f0 augu af e\u00f0lilegri st\u00e6r\u00f0 og sj\u00f3nhimnur sem starfa e\u00f0lilega. MitfMi-Wh\/+ og MitfMi-Wh\/Mitfmi m\u00fds s\u00fdndu sk\u00fdr merki alvarlegrar sj\u00f3nhimnuhr\u00f6rnunar vi\u00f0 3 m\u00e1na\u00f0a aldur. OCT snei\u00f0myndir fr\u00e1 1 og 3 m\u00e1na\u00f0a g\u00f6mlum MitfK243R\/K243R; Tyr::Cre m\u00fasum s\u00fdna a\u00f0 sum sv\u00e6\u00f0i sj\u00f3nhimnu \u00feeirra hafa lit\u00feekju, lj\u00f3snema og frumul\u00f6g taugafrumna \u00f3breytt, me\u00f0an \u00ed a\u00f0liggjandi sv\u00e6\u00f0um er hr\u00f6rnun \u00feessara frumna. Vi\u00f0 eins \u00e1rs aldur eru lit\u00feekja, lj\u00f3snemalag og ytri frumul\u00f6g sj\u00f3nhimnu horfin \u00ed MitfK243R\/K243R; Tyr::Cre m\u00fasum. Magnm\u00e6ling me\u00f0 Western-blettun s\u00fdndi a\u00f0 l\u00edp\u00ed\u00f0-f\u00e6rt LC3B-II, sem er nota\u00f0 sem merki fyrir sj\u00e1lfs\u00e1t, var markt\u00e6kt auki\u00f0 \u00ed \u00f3me\u00f0h\u00f6ndlu\u00f0um lit\u00feekjufrumum \u00far Mitfmi-vga9\/+ m\u00fasum.\u00a0 Enn fremur s\u00e1st \u00ed rafeindasm\u00e1sj\u00e1rmyndum a\u00f0 Mitfmi-vga9\/+ m\u00fds hafa aukinn fj\u00f6lda sj\u00e1lfs\u00e1tsagna (autolysosomes) \u00ed lit\u00feekju bori\u00f0 saman vi\u00f0 augu villiger\u00f0arm\u00fasa vi\u00f0 \u00feriggja m\u00e1na\u00f0a aldur. \u00deetta bendir til \u00f3e\u00f0lilegs sj\u00e1lfs\u00e1ts \u00ed lit\u00feekju Mitfmi-vga9\/+ m\u00fasa me\u00f0 upps\u00f6fnun \u00f3virkra sj\u00e1lfs\u00e1tsagna. Ni\u00f0urst\u00f6\u00f0urnar s\u00fdna a\u00f0 Mitf st\u00f6kkbreytingarnar hafa \u00e1hrif \u00e1 starfsemi sj\u00f3nhimnu, byggingu taugavefs sj\u00f3nhimnu og \u00e1 lit\u00feekju \u00ed \u00f3l\u00edkum m\u00e6li eftir \u00fev\u00ed um hvers konar st\u00f6kkbreytingu er a\u00f0 r\u00e6\u00f0a og a\u00f0 geni\u00f0 gegnir lykilhlutverki \u00ed a\u00f0 st\u00fdra litdreifingu \u00ed augnbotnum m\u00fasa.\u00a0 M\u00fds me\u00f0 \u201eskilyrtu\u201c MitfK243R; Tyr::Cre st\u00f6kkbreytinguna er hugsanlega fyrsta m\u00fasal\u00edkani\u00f0 af h\u00e6gvaxandi, sv\u00e6\u00f0isbundinni hr\u00f6rnun sj\u00f3nhimnu (geographic atrophy, GA).\u00a0 A\u00f0 auki kom \u00ed lj\u00f3s a\u00f0 Mitf geni\u00f0 gegnir mikilv\u00e6gu hlutverki \u00ed sj\u00e1lfs\u00e1ti \u00ed lit\u00feekju m\u00fasa.\u00a0 \u00deetta verkefni hefur varpa\u00f0 lj\u00f3si \u00e1 hlutverk Mitf \u00ed starfsemi augans og lagt grunn a\u00f0 n\u00fdju d\u00fdra-l\u00edkani af GA.<\/p>\n

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

The mouse microphthalmia-associated transcription factor (Mitf) gene is crucial for the normal development and function of the retinal pigment epithelium (RPE) in mice. Loss of function mutations in this gene can cause ocular hypopigmentation, microphthalmia and blindness. The cellular clearance pathway autophagy is important for the homeostasis of RPE cells. Impaired or dysfunctional autophagy has been associated with age-related macular degeneration (AMD). The purpose of this study was to characterize the effects of specific mutations in the Mitf gene on the morphology and function of the retina and RPE and to determine whether Mitf regulates autophagy in mouse primary RPE cells. The following Mitf mutations were used: Mitfmi-vga9\/+, Mitfmi-enu22(398)\/Mitfmi-enu22(398), MitfMi-Wh\/+, MitfMi-Wh\/Mitfmi, MitfK243R;Tyr::Cre and wild type (C5BL\/6J) mice as a control. All the Mitf mutant mice examined revealed some hypopigmentation in their fundi, varying in degree. Mitfmi-vga9\/+ and Mitfmi-enu22(398)\/Mitfmi-enu22(398) mice have normal eye size and external structures and normally functioning retinas. In contrast, MitfMi-Wh\/+ and MitfMi-Wh\/Mitfmi showed clear evidence of severe retinal degeneration at 3 months of age. Interestingly, MitfK243R\/K243R; Tyr::Cre mice showed a different eye color on the right eye, whereas the left eye showed a brighter appearance. OCT images from 1 and 3 month old MitfK243R\/K243R;Tyr::Cre mice demonstrated geographic areas while other regions were normal. However, at one year of age the RPE, photoreceptor and outer retina layers were missing from the eyes of MitfK243R\/K243R;Tyr::Cre mice.<\/p>\n

Immunoblotting analysis showed that the autophagy marker LC3B-II was significantly increased in untreated Mitfmi-vga9\/+ mouse primary RPE cells, suggesting that autophagy flux is affected in these cells. Furthermore, electron micrographs deomonstrated that Mitfmi-vga9\/+ RPE cells have an increased number of autolysosomes (ALs) compared to 3 month old wild type mice, suggesting that dysfunctional autophagy in the Mitfmi-vga9\/+\u00a0 RPE leads to an accumulation of inactive ALs. \u00a0The results show that the Mitf gene has an impact on retinal function, the morphology of the neuroretina and the RPE to a varying degree, depending on the mutations involved and plays a fundamental role in regulating the fundus pigmentation in mice. We have found that mice with the MitfK243R conditional mutation driven by the Tyr::Cre driver may be the first mouse model of slow progressive retinal geographic atrophy (GA). In addition, we have shown that Mitf plays an important role in autophagy in mice. This work has shed light on the role of Mitf in eye function and built a foundation for a novel model of GA.\u00a0<\/strong><\/p>\n

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

Andrea Garc\u00eda-Llorca er f\u00e6dd \u00ed Alicante \u00e1 Sp\u00e1ni \u00e1ri\u00f0 1987. H\u00fan lauk BS-pr\u00f3fi \u00ed l\u00edffr\u00e6\u00f0i vi\u00f0 IE Universidad \u00ed Segovia \u00e1 Sp\u00e1ni \u00e1ri\u00f0 2005, og BS-pr\u00f3fi \u00ed l\u00edfefnafr\u00e6\u00f0i vi\u00f0 Universidad de Salamanca \u00e1 Sp\u00e1ni \u00e1ri\u00f0 2009.\u00a0 H\u00fan lauk meistarapr\u00f3fi \u00ed kennslufr\u00e6\u00f0um \u00e1 framhaldsn\u00e1msstigi, me\u00f0 s\u00e9rh\u00e6fingu \u00ed l\u00edffr\u00e6\u00f0i og jar\u00f0fr\u00e6\u00f0i fr\u00e1 Universidad de Salamanca \u00e1ri\u00f0 2013. \u00cd lok \u00e1rsins 2014 h\u00f3f Andrea Garc\u00eda-Llorca doktorsn\u00e1m vi\u00f0 L\u00edfe\u00f0lisfr\u00e6\u00f0istofnun L\u00e6knadeildar H\u00cd.<\/p>\n<\/div><\/div>","protected":false},"featured_media":1114,"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":"2020-02-18T13:00:00+00:00","_phd_date_end":"2020-02-18T16:00:00+00:00","_phd_location":"A\u00f0albygging H\u00e1t\u00ed\u00f0asalur","_phd_admission":"A\u00f0gangur \u00f3keypis","_phd_thesis_title":"Umritunar\u00fe\u00e1tturinn microphthalmia-associated transcription factor (Mitf) og hlutverk hans \u00ed starfsemi augna m\u00fasa. 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