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dc.contributor.advisorErsdal, Cecilie
dc.contributor.advisorTranulis, Michael A
dc.contributor.advisorEspenes, Arild
dc.contributor.authorSalvesen, Øyvind
dc.date.accessioned2018-05-29T12:53:26Z
dc.date.available2018-05-29T12:53:26Z
dc.date.issued2017
dc.identifier.isbn978-82-575-1747-2
dc.identifier.issn1894-6402
dc.identifier.urihttp://hdl.handle.net/11250/2499636
dc.description.abstractThe cellular prion protein (PrPC) is known for its pivotal role in the development of prion diseases, such as Creutzfeldt-Jakob disease in humans and scrapie in small ruminants. In these diseases, PrPC is converted into a pathological form, PrPSc. The accumulation of this misfolded isoform in the brain results in fatal neurodegeneration. Several decades of research have revealed clues to the normal biological function of PrPC, yet still without a definite conclusion. Unravelling normal PrPC biology is important not only to understand the pathogenesis of prion disorders, but also to identify potential side effects of future treatments involving blocking of PrPC or removal of the PrPC-encoding gene (PRNP). We utilized a unique line of Norwegian dairy goats that carry a stop mutation early in the PRNP to study PrPC physiology. These goats are the only known mammals that are naturally devoid of PrPC (PRNPTer/Ter). By using next generation RNA sequencing, we identified a primed state of interferon-stimulated genes in circulating blood cells and tissues of PRNPTer/Ter goats (Papers II, III, and IV). When exposed to systemic lipopolysaccharide (LPS), PrPC-deficient goats suffered a prolonged sickness behavior and displayed an expression profile skewed towards a type I interferon signaling response in the brain (Paper III). In the lungs, a tissue with a more severe response to LPS, loss of PrPC resulted in increased activation of pro-inflammatory pathways and remodeling of the extracellular matrix (Paper IV), which indicates augmented damage to the lung parenchyma. Taken together, we propose that PrPC is a modulator of inflammatory pathways, particularly downstream of type I interferons, and protects vulnerable tissues against inflammatory stress. Being located at the cell surface, our findings corroborate the theory of PrPC as a scaffolding protein, which can interact with various forms of multiprotein complexes and regulate downstream signaling. In addition to exploring the function of PrPC, the current thesis extends the existing knowledge of the inflammatory response in small ruminants. Systemic administration of LPS mimics the initial events of sepsis and is a well-established method of studying the innate immune system. We provide evidence that both leukocytes and tissues increase transcription of acute-phase protein genes at the beginning of an inflammation, and we identify SAA3 as a particularly useful biomarker (Papers I, III, and IV). In the choroid plexus, a profound activation of the transcriptome and increased number of Iba1-positive cells were observed. Being located at the blood-brain interface, we confirm that this tissue plays a crucial role in the interaction between systemic circulation and the brain. Alterations in the hippocampus transcriptome were mild, which suggests that this brain region is relatively protected from circulating endotoxins. Yet, the clinical response and activation of astrocytes confirms that inflammation was present (Paper III). As described in paper IV, the lungs were the most affected organ, characterized by substantial activation of the transcriptome and morphological changes compatible with acute lung injury. The high pulmonary sensitivity of goats towards systemic endotoxins implies that limiting pulmonary inflammation is of special importance for treating septic patients. In light of the increasing problem of antimicrobial resistance against antibiotics, understanding the molecular mechanisms of inflammation is a prerequisite for designing new therapeutic strategies.nb_NO
dc.description.abstractDet normale prionproteinet (PrPC) finnes hos alle pattedyr og er kjent for sin rolle i utviklingen av prionsykdommer. Disse inkluderer blant annet Creutzfeldt-Jakobs sykdom hos mennesker, skrantesjuke (CWD) hos hjortedyr, og skrapesjuke (scrapie) hos småfe. Sykdommene skyldes at en unormal, feilfoldet variant av prionproteinet (PrPSc) akkumulerer i sentralnervesystemet og fører til degenerasjon av nerveceller. Prionsykdommer kan ikke behandles og er alltid dødelige. Flere tiår med forskning har indikert at PrPC er involvert i en rekke normale biologiske funksjoner, men noen endelig konklusjon har uteblitt. Kartlegging av PrPC sin fysiologiske funksjon er viktig for å forstå utviklingen av prionsykdommer, samt å identifisere potensielle bivirkninger av framtidige behandlingsformer som kan involvere blokkering av PrPC eller fjerning av genet som koder for prionproteinet (PRNP).nb_NO
dc.language.isoengnb_NO
dc.publisherNorwegian University of Life Sciences, Åsnb_NO
dc.relation.ispartofseriesPhD Thesis;2017:81
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/deed.no*
dc.subjectGoatsnb_NO
dc.subjectLipopolysaccharide (LPS)nb_NO
dc.subjectSickness behaviornb_NO
dc.titleThe cellular prion protein and the inflammatory responsenb_NO
dc.typeDoctoral thesisnb_NO
dc.relation.projectNorges forskningsråd: 227386/E40nb_NO


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