{"id":6358,"date":"2026-10-19T09:48:48","date_gmt":"2026-10-19T09:48:48","guid":{"rendered":"https:\/\/phd.hi.is\/doktorsvorn\/doktorsvorn-i-laeknavisindum-salvor-rafnsdottir\/"},"modified":"2026-10-19T09:48:48","modified_gmt":"2026-10-19T09:48:48","slug":"doktorsvorn-i-laeknavisindum-salvor-rafnsdottir","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-laeknavisindum-salvor-rafnsdottir\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed l\u00e6knav\u00edsindum – Salv\u00f6r Rafnsd\u00f3ttir"},"content":{"rendered":"
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F\u00f6studaginn 5. apr\u00edl 2024 ver Salv\u00f6r Rafnsd\u00f3ttir doktorsritger\u00f0 s\u00edna \u00ed l\u00e6knav\u00edsindum vi\u00f0 L\u00e6knadeild H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: \u00c1hrif utangenaerf\u00f0a \u00e1 k\u00e6lisvar spend\u00fdrafrumna. Epigenetic insights into the mammalian mild hypothermia response.<\/p>\n

Andm\u00e6lendur eru dr. Anne Willis, pr\u00f3fessor vi\u00f0 University of Cambridge, og dr. Zophon\u00edas Oddur J\u00f3nsson, pr\u00f3fessor vi\u00f0 L\u00edf-og umhverfisv\u00edsindadeild H\u00cd.<\/p>\n

Umsj\u00f3narkennari og lei\u00f0beinandi var Hans T\u00f3mas Bj\u00f6rnsson, pr\u00f3fessor. Auk hans s\u00e1tu Eir\u00edkur Steingr\u00edmsson, pr\u00f3fessor, Erna Magn\u00fasd\u00f3ttir, d\u00f3sent, Martin Ingi Sigur\u00f0sson og Sesselja Sigurborg \u00d3marsd\u00f3ttir, pr\u00f3fessorar \u00ed doktorsnefnd.<\/p>\n

Dr. S\u00e6d\u00eds S\u00e6varsd\u00f3ttir, pr\u00f3fessor og varadeildarforseti L\u00e6knadeildar, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed H\u00e1t\u00ed\u00f0arsal H\u00e1sk\u00f3la \u00cdslands og hefst kl. 09:00.<\/p>\n

\u00c1grip<\/strong><\/p>\n

\u00deekkt er a\u00f0 k\u00e6ling frumna (32-36\u00b0C) eykur tj\u00e1ningu f\u00e1einna \u00feekktra gena. Margt er \u00e1 huldu um \u00fe\u00e1 innanfrumu- og millifrumuferla sem k\u00e6ling virkjar og kalla\u00f0ir hafa veri\u00f0 k\u00e6lisvari\u00f0. K\u00e6ling er notu\u00f0 \u00ed l\u00e6knisfr\u00e6\u00f0ilegum tilgangi til a\u00f0 f\u00e1 fram taugaverndandi \u00e1hrif hj\u00e1 sj\u00faklingum sem hafa or\u00f0i\u00f0 fyrir miklum taugaska\u00f0a, svo sem eftir hjartastopp e\u00f0a vegna s\u00farefnis\u00feurr\u00f0ar \u00ed f\u00e6\u00f0ingu.\u00a0<\/p>\n

K\u00e6liv\u00edsar (mild hypothermia indicators (MHI)) voru b\u00fanir til en \u00feeir segja til um tj\u00e1ningu \u00feriggja gena (SP1, CIRBP, RBM3) sem \u00feegar eru \u00feekkt a\u00f0 \u00fev\u00ed a\u00f0 gegna hlutverki \u00ed k\u00e6lisvarinu. \u00deessir k\u00e6liv\u00edsar voru nota\u00f0ir til a\u00f0 framkv\u00e6ma lyfjaskimun me\u00f0 SP1+MCRE-MHI k\u00e6liv\u00edsi \u00ed leit a\u00f0 virkjun k\u00e6lisvarsins me\u00f0al 1953 lyfja. Tv\u00f6 lyf (Poziotinib og Entacapone) fundust sem b\u00e6\u00f0i vir\u00f0ast geta virkja\u00f0 k\u00e6lisvari\u00f0. N\u00e6st voru k\u00e6liv\u00edsarnir, SP1-MHI og Lenti-RBM3-MHI, nota\u00f0ir me\u00f0 frams\u00fdnni CRISPR-Cas9-st\u00f6kkbreytiskimun til \u00feess a\u00f0 finna gen sem virkja e\u00f0a b\u00e6la k\u00e6lisvari\u00f0. M\u00f6rg gen fundust sem vir\u00f0ast geta virkja\u00f0 e\u00f0a b\u00e6lt k\u00e6lisvari\u00f0 en sta\u00f0fest var hlutverk eins sl\u00edks gens sem b\u00e6lir k\u00e6lisvari\u00f0, SMYD5. SMYD5 minnkar vi\u00f0 32\u00b0C \u00ed mannafrumum og \u00ed heila m\u00fasa og s\u00fdnir minnka\u00f0a bindingu vi\u00f0 erf\u00f0amengi\u00f0 vi\u00f0 32\u00b0C \u00ed mannafrumum. Einnig var RNA ra\u00f0greining framkv\u00e6md \u00e1 taugastofnfrumum \u00far m\u00fasum \u00ed r\u00e6kt vi\u00f0 37\u00b0C og 32\u00b0C, og frumum \u00far dreka \u00e1samt heilaberki m\u00fasa sem annars vegar h\u00f6f\u00f0u innra hitastig 37\u00b0C og hins vegar innra hitastig vi\u00f0 32\u00b0C. \u00cd lj\u00f3s kom a\u00f0 m\u00f6rg gen breyta tj\u00e1ningu sinni vi\u00f0 k\u00e6lingu. \u00derj\u00e1t\u00edu og sj\u00f6 \u00f6nnur gen fundust sem SMYD5 vir\u00f0ist b\u00e6la vi\u00f0 37\u00b0C og haga s\u00e9r \u00fev\u00ed \u00e1 svipa\u00f0an m\u00e1ta og SP1. Loks var framkv\u00e6md frams\u00fdn ENU st\u00f6kkbreytiskimun \u00e1 m\u00fasum, til \u00feess a\u00f0 finna gen sem valda afbrig\u00f0ilegri hitastigsstj\u00f3rnun vi\u00f0 k\u00e6li\u00e1reiti og birtum lista yfir l\u00edkleg hitastigsstj\u00f3rnandi gen.<\/p>\n

\u00deetta verkefni hefur auki\u00f0 skilning \u00e1 k\u00e6lisvari spend\u00fdrafrumna, en m\u00f6rg gen breyta tj\u00e1ningu sinni vi\u00f0 k\u00e6lingu e\u00f0a hafa \u00e1hrif \u00e1 grunnl\u00edkamshitastig l\u00edfvera eftir k\u00e6lingu. \u00cd \u00feessari doktorsritger\u00f0 kemur fram hvernig k\u00e6ling fyrir tilstu\u00f0lan utangenaerf\u00f0a getur haft \u00e1hrif \u00e1 genatj\u00e1ningu. Einnig fundust tv\u00f6 lyf sem m\u00f6gulega geta haft \u00e1hrif \u00e1 k\u00e6lisv\u00f6run, en \u00fea\u00f0 b\u00fd\u00f0ur upp \u00e1 frekari m\u00f6guleika til ranns\u00f3kna \u00e1 lyfjame\u00f0fer\u00f0um hj\u00e1 sj\u00faklingum sem \u00feurfa \u00e1 k\u00e6lime\u00f0fer\u00f0 a\u00f0 halda.<\/p>\n

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

In humans, the expression of several genes is increased with mild hypothermia (32-36\u00b0C), however, the precise nature of this mild hypothermia response (MHR) is unknown. In clinical practice MHR is often utilized as a neuroprotective agent in catastrophic events such as after neonatal hypoxic ischemia and cardiac arrest.<\/p>\n

In this thesis there were several methods used to gain deeper understanding of some of the characteristics of the MHR. To study these effects there were created and validated several fluorescent mild hypothermia indicators (MHI) which measure regulatory activity of three genes (SP1, CIRBP, RBM3) which have previously been shown to be part of the MHR. To gain further insight into the MHR the MHIs were utilized for two of three different screening strategies. The SP1+MCRE-MHI was used to look for MHR activation after medication exposure to 1953 FDA-approved compounds. This yielded two agents (Poziotinib and Entacapone) that could activate the MHR. Next, a forward CRISPR-Cas9 mutagenesis screen was combined with two MHIs, SP1-MHI and Lenti-RBM3-MHI, to identify a list of potential activators\/repressors of SP1 and RBM3. This led to the identification of numerous activators and repressors, including the repressor SMYD5 which was robustly validated. SMYD5 protein amounts and genomic binding decreases at 32\u00b0C in vivo and in vitro. RNA-Sequencing was performed of in vitro mouse Neural Progenitor cells (mNPCs) at 37\u00b0C and 32\u00b0C as well as RNA-sequencing of in vivo mouse hippocampal and cortical cells that had their core temperature either kept at 37\u00b0C or lowered to 32\u00b0C. There are many genes that have altered expression under hypothermic conditions. A list of additional 37 temperature responsive genes were identified; these genes seem to be regulated in a similar temperature dependent manner as SP1 and CIRBP by SMYD5. Finally, a dominant ENU mutagenesis screen was performed to look for genes that cause abnormality in core temperature under hypothermic stimulus. The first results are promising, and this thesis provides a list of candidate genes that could cause core temperature abnormality, although the list needs further validation.<\/p>\n

This project expands the current knowledge of the mild hypothermia pathway in mammalian cells and mammals. Here in this thesis, we provide a mammalian example of how the epigenetic machinery incorporates the influence of environmental cues into the genome of mammalian cells. Also, our study has revealed novel therapeutic avenues for targeted temperature management\/therapeutic hypothermia through pharmacological means.<\/p>\n

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

Salv\u00f6r Rafnsd\u00f3ttir er f\u00e6dd \u00e1ri\u00f0 1993 \u00ed Edinborg \u00ed Skotlandi. H\u00fan \u00fatskrifa\u00f0ist af n\u00e1tt\u00farufr\u00e6\u00f0ibraut Menntask\u00f3lans \u00ed Reykjav\u00edk \u00e1ri\u00f0 2013. Salv\u00f6r lauk BS-pr\u00f3fi og kand\u00eddatspr\u00f3fi \u00ed l\u00e6knisfr\u00e6\u00f0i fr\u00e1 H\u00e1sk\u00f3la \u00cdslands \u00e1rin 2016 og 2019. Doktorsn\u00e1m hennar vi\u00f0 H\u00e1sk\u00f3la \u00cdslands h\u00f3fst sumari\u00f0 2019. Me\u00f0fram n\u00e1minu kl\u00e1ra\u00f0i Salv\u00f6r kand\u00eddats\u00e1r \u00ed l\u00e6knisfr\u00e6\u00f0i. Salv\u00f6r var vori\u00f0 2021 Fulbright Visiting Student Researcher vi\u00f0 Johns Hopkins University \u00ed Bandar\u00edkjunum. Foreldrar Salvarar eru Rafn Benediktsson og Hildur Kristj\u00e1nsd\u00f3ttir. Salv\u00f6r er gift Kristj\u00e1ni Godsk R\u00f6gnvaldssyni l\u00e6kni og saman eiga \u00feau einn dreng, St\u00edg.<\/p>\n<\/div><\/div>","protected":false},"featured_media":5674,"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":"2024-04-05T09:00:00+00:00","_phd_date_end":"2024-04-05T12:00:00+00:00","_phd_location":"A\u00f0albygging","_phd_admission":"A\u00f0gangur \u00f3keypis","_phd_thesis_title":"\u00c1hrif utangenaerf\u00f0a \u00e1 k\u00e6lisvar spend\u00fdrafrumna. 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