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Forskere har lenge debattert om spesifikke endringer i måten genene våre reguleres på, kalt epigenetiske endringer eller "epimutasjoner," kan øke risikoen for kreft. Våre nylige banebrytende undersøkelser har gitt sterke bevis på at epimutasjoner faktisk er en risikofaktor for visse typer kreft.
I en studie av en stor gruppe kvinner fant vi at de som hadde epimutasjoner i BRCA1-genet, hadde mye større risiko for å utvikle trippel-negativ brystkreft og høygradig serøs eggstokkreft senere i livet. Disse epimutasjonene ser ut til å oppstå tidlig under fosterutviklingen, og fører til at det fødte barnet (og senere det voksne individet) har en mosaikk av celler i kroppen, der noen få celler bærer epimutasjonen.
Nå har vi som mål å utvide disse studiene til andre gener og andre former for kreft. For å gjøre dette vil vi analysere blodprøver fra en studie som har rekruttert over 160 000 kvinner i USA.
Hvis denne forskningen lykkes, kan den revolusjonere vår forståelse av hvordan kreft utvikler seg og føre til bedre forebyggende tiltak. Det kan også ha store implikasjoner for kreftscreeningprogrammer og genetisk veiledning for personer med høy risiko for visse typer kreft.
Alt i alt fremhever vår forskning den viktige rollen som epigenetiske endringer kan spille i kreftutvikling og understreker behovet for ytterligere undersøkelser på dette området.

Cancers result from accumulation of genetic and epigenetic alterations. The minority of cancers are due to inherited (germline) alterations that affect all cells in the body. On the other hand, the majority of cancers (>85%; sporadic cancers) are believed to occur due to localised alterations that accumulate after birth as a result of stochastic processes and/or environmental effects. Recently, in a major breakthrough work, we have provided definitive evidence that some sporadic cancers arise in adult life due to mosaic BRCA1 epimutations that occurred during the early embryonic development. BRCA1 epimutations have a surprisingly high population frequency (>5% of adult women) and hazard ratios for breast and ovarian cancer (2.4 and 1.9, respectively). Together with the findings of epimutations in other tumour suppressor genes (MGMT, MLH1, etc) this has led us to hypothesise that a substantial fraction of other sporadic cancers can be attributed to prenatal epimutations in other tumour suppressor genes.

In this project, we will use ultradeep targeted methylation sequencing for quantitative and qualitative analyses of epimutations. Evaluation of cancer risk related to epimutations will be done by studying samples from prospective biobanks (WHI) with samples from healthy women that remained cancer-free or developed different types of incident cancers years/decades after samples were taken. We will also characterise epimutations present in samples of newborn boys and girls, as well as their parents (MoBa biobank). Finally, using cryopreserved blood-derived stem-like cells from young healthy males and female breast cancer patients (in-house biobank), we will assess mutational and epimutational mosaicism at the single-cell level, generating clonal phylogeny for the methylated cells and thus providing insights on early-developmental processes that create epimutations.

Mosaic epimutations: population prevalence, mechanistic origins, and their role in cancer

Cøliaki er en sykdom som rammer 1-2% av befolkningen. Den eneste eksisterende behandlingen for sykdommen i dag er en livslang glutenfri kost. Det er ønskelig å utvikle alternative behandlingsmetoder. Nyere forskning har avdekket at enzymet transglutaminase 2 spiller en sentral rolle i utviklingen av sykdommen. Dette enzymet forandrer glutenproteiner slik at immunsystemet hos cøliakere kan reagerer på disse proteinene. Denne immunresponsen hos cøliakere involverer B-celler. B-celler produserer antistoffer, og cøliakere har B-celler og antistoffer som er rettet mot transglutaminase 2. I projektet ønsker vi å ta denne kunnskapen i retning mot utvikling av nye behandlingsprinsipper. En del av prosjektet dreier seg om hemming av enzymaktiviteten til transglutaminase 2, og å avdekke hvor i kroppen hvor transglutaminaseaktiviteten bør hemmes. En annen del av prosjektet dreier seg om å finne en metode som kan elimimere B-cellene som gjenkjenner transglutaminase 2.  Prosjektet vil studere celler og vev fra cøliakere samt mus som er genetisk modifisert til å uttrykke reseptorer som brukes av cøliakere til å gjenkjenne gluten og transglutaminase 2.

Celiac disease is a prevalent autoinflammatory condition caused by immune reaction to dietary gluten proteins. The only available treatment is lifelong avoidance of dietary gluten. However, symptoms and enteropathy often persist in patients who attempt to adhere to a gluten-free diet. Thus, there is a need to develop non-dietary therapies for celiac disease. 

The enzyme transglutaminase 2 (TG2) has critical roles in celiac disease pathogenesis. The enzymatic activity of TG2 creates by deamidation gluten peptides that have high affinity for disease-predisposing HLA-molecules, and these deamidated peptides are recognized by the disease-driving CD4+ T cells. Moreover, TG2 is the target of a highly specific autoantibody response. In this project we will explore two novel treatment avenues focused on TG2. In the first approach, we seek to develop novel immunotherapeutic molecules, Bispecific AutoAntigen T-cell Engagers (BiAATEs), to specifically eliminate the subset of autoreactive TG2-specific B cells while avoiding general immunosuppression. The results will be important not only for celiac disease but also for other autoimmune diseases having cytosolic autoantigens.

Second, we will explore therapeutic inhibition of TG2. ZED1227, an irreversible inhibitor of TG2, was recently shown in a phase 2 clinical trial to prevent gluten-induced intestinal damage in celiac disease patients. It is however unknown where in the body the drug is active. Our group has obtained evidence that the gut lumen likely is the relevant site where TG2 is active and encounters gluten peptides for deamidation. We will test the new hypothesis that TG2 in gut lumen is pathogenic in celiac disease and will explore inhibition of gut luminal TG2 as therapy.  

Both arms of the project will combine studies on patient samples with mechanistic experiments in state-of-the art humanized mouse models that we recently developed.

Exploring novel therapies for celiac disease centered around the autoantigen transglutaminase 2

Kreftvev inneholder ikke bare kreftceller, men også en rekke forskjellige immunceller. Noen av dem er nyttige, andre bytter side og hjelper nå svulsten. Kunnskapen om fordelingen av immuncelletyper til en pasient er svært viktig. Denne informasjonen er med på å definere den beste personlige behandlingen, gi en klarere overlevelsesprognose eller hjelper å definere nye mulige behandlingsalternativer. 
I tillegg gjennomgår immunceller i tumormikromiljøet flere endringer, noen er nyttige i kampen mot kreft, andre hjelper svulsten til å vokse eller spre seg. Kunnskapen om disse endringene i de ulike immuncelletypene hjelper til med å forklare prosessene i svulsten eller til å oppdage mulige nye biomarkører for behandlingsalternativer. 
I dette prosjektet ønsker vi å ta hensyn til både den romlige fordelingen og endringene av de forskjellige immuncelletypene avhengig av deres lokalisering i forhold til kreftvev. Hvilke endringer kan vi finne? Hvordan påvirker de hverandre og hvordan påvirkes de av svulsten? Vi ønsker å bruke denne kunnskapen til å oppdage nye mulige biomarkører for behandlingsalternativer.

Spatial transcriptomics provides unprecedented details about the molecular mechanisms that take place within and between cells. ST assesses the molecular content of well-defined regions in a tissue which potentially cover contributions from multiple cells. In order to draw correct biological conclusions from ST analysis, spatial distributions of individual cell types are a prerequisite. This generates an urgent need for computational methods addressing this question. However, computational estimates of cellular compositions from ST are complicated by several factors. First, the methods require well curated data which is usually not available; every specimen has its own individual characteristics and so, every tissue type or even every patient, might require a own, comprehensively verified model. Second, data is noisy, making estimates prone to errors. Moreover, even if a computational model is designed for a specific tissue or even patient, it might be miss-specified, leading to additional systematic errors. In this project, we will develop a toolbox called Computational Dissection of Cellular Distributions (CDCD), which directly accounts for these issues. CDCD will advance the state of the art by (1) taking into account a priori unknown, hidden cellular background contributions, (2) taking into account environmental factors (i.e., tissue and patient dependence), and by (3) comprehensive errors estimation. Intriguingly, in contrast to available techniques, CDCD will facilitate estimates of cellular regulation in space! Such gene-regulation gradients will allow us to address questions of how immune cells adapt their molecular phenotype with respect to their environment. Additionally we will verify our algorithms on a conjoint norwegian phase II melanoma case study. CDCD will be made freely available via easy-to-use webpage and software solution, enabling both expert bioinformaticians and wet-lab biologists an efficient use of the to-be-developed methodology.

Computational dissection of cellular distributions and cell-type specific regulation patterns from spatial transcriptomics data

I møte med utfordringene ved en aldrende befolkning i Europa, utvikler dette prosjektet bærekraftige øyedråper basert på hydrogeler utvunnet fra plantebaserte forbindelser, for å motvirke aldersrelaterte forandringer i netthinnen.

De bio-baserte hydrogelene er utviklet for å fjerne skadelige avleiringer, redusere betennelsestilstander og forbedre oksygentilførselen til netthinnen – faktorer som er sentrale for å bevare synet og opprettholde cellenes energiomsetning.

I motsetning til eksisterende behandlinger benytter denne tilnærmingen miljøvennlige materialer og unngår invasive prosedyrer, noe som gir en tryggere og mer tilgjengelig løsning for personer med aldersrelaterte øyesykdommer.

Sustainable self-cleaning hydrogels in ophthalmology

Antibiotikaresistens er i ferd med å bli en alvorlig global helsetrussel. Etter hvert som bakterier utvikler motstand mot dagens medisiner, blir infeksjoner som tidligere var enkle å behandle, igjen livstruende. 
Verdens helseorganisasjon (WHO) har laget en liste over farlige bakterier hvor behovet for nye antibiotika er akutt. Dessverre er de fleste antibiotika som utvikles i dag bare små endringer av gamle medisiner – og bakteriene lærer raskt å stå imot disse også.

For å løse dette problemet må vi finne helt nye måter å angripe bakteriene på. Det betyr at vi må oppdage nye angrepsmål i bakteriene og utvikle antibiotika som kan nå frem til og slå ut disse.

Dette prosjektet har som mål å gjøre nettopp det. Et internasjonalt team av forskere samarbeider for å:

Undersøke to spesifikke bakterieenzymer for å se om de kan være gode angrepsmål for fremtidige antibiotika.
Bidra til å øke vår forståelse av hvordan antibiotiske legemidler kommer seg inn i bakteier, noe som er en av de største utfordringene i utviklingen av nye antibiotika.
Vi fokuserer på tre typer skadelige bakterier: Pseudomonas aeruginosa, Escherichia coli og Klebsiella pneumoniae. Disse er alle såkalte «Gram-negative» bakterier, som er spesielt vanskelige å behandle på grunn av deres oppbygning.

I prosjektet vil vi studere to viktige enzymer som disse bakteriene bruker til å lage fettsyrer – molekyler de trenger for å overleve. Ved bruk av ulike teknikker skal vi designe og teste nye inhibitorer som kan blokkere disse enzymene. Samtidig skal vi undersøke hvordan disse inhibitorene kommer seg inn i bakteriene, slik at vi er sikre på at de faktisk når frem til målet sitt.

Ved å kombinere kjemi, biologi og legemiddeldesign vil dette prosjektet ikke bare hjelpe oss med å komme videre på veien til å finne nye antibiotika – det vil også gi verdifull innsikt i hvordan vi kan utvikle bedre antibiotika i fremtiden.

There is an urgent need for new antibiotics to prevent the looming crisis of antimicrobial resistance and WHO has published a list of bacteria for which antibiotics are in high demand and urged that research and drug discovery efforts are directed toward these. Antibiotics are a prerequisite for modern medicine, however, most of the compounds in clinical development are not fit for purpose at they are derivatives of already known antibiotics and therefore have cross-resistance with existing agents.
To tackle this crisis, we need fundamental knowledge on new targets for antibiotics, and we need compounds that can get into bacteria and work on these targets. This project will address this 1) by delivering potent inhibitors on two proposed bacterial protein targets to establish if they are promising targets for future antibiotics and 2) by establishing relationships between compound properties and uptake in bacteria. To reach these highly ambitious goals, we have assembled an interdisciplinary and international team of experts in antibiotic drug discovery, protein dynamics, structure-based drug design, covalent enzyme inhibition, organic synthesis and medicinal chemistry. We will explore two essential enzymes involved in fatty acid synthesis in Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, Gram-negative bacteria for which WHO has stated that new antibiotics are critically needed. We will use a structure-based approach to develop potent inhibitors for chemical target validation. This process will be guided by experimental data about uptake into bacteria to ensure that our compounds reach their targets, a critical step in chemical target validation. Through this we will provide crucial information to advance our understanding of the compound properties that governs uptake in Gram-negative bacteria. This will deliver far-reaching insights, not only for the studied target but antibiotic drug discovery in general.

Validating fatty acid synthesis enzymes as targets for antibiotics against Pseudomonas aeruginosa and other Gram-negative bacteria.

Dette prosjektet har som mål å undersøke nervedannelse i primær brystkreft og hjernemetastaser fra brystkreft. Vår hypotese er at en undergruppe av aggressive brystkreftsvulster involverer nervestrukturer for å fremme tumorprogresjon, inkludert metastaser til hjernevev, som er den mest nevrogene nisjen i kroppen.

Hos kvinner er brystkreft den hyppigste kreftsykdommen og den ledende årsaken til kreftrelaterte dødsfall verden over. Trippel-negativ eller basaloid brystkreft er de mest utfordrende subgruppene, på grunn av mangel på effektive behandlingsmål. Studier av nervefiber-tetthet i brystkreft har vist at høyt innerverte svulster er mer aggressive, og tilstedeværelse av nerve-elementer er assosiert med økt metastasering og forverret pasientprognose. Våre foreløpige data, fra vevsanalyse av to brystkreftserier, bekrefter disse funnene. Vi anser derfor nerveinvolvering som en ny og lovende biomarkør i vår forståelse av aggressiv brystkreft.

Nerver er små fiber-strukturer i svulster, som nåler i en høystakk, og vanskelig å oppdage ved vanlig mikroskopisk undersøkelse. Derfor eksisterer det ikke automatiserte prosedyrer for deteksjon av slike svulst-nerver, og nervene sin klinisk-patologiske betydning er lite kjent. I dette prosjektet vil vi utvikle mer sensitive metoder for å påvise små nerveelementer i vev fra svulster, ved hjelp av avansert bildeteknologi. Interaksjon mellom kreftceller og nerver vil bli analysert i funksjonelle studier.

Vår hypotese er at aggressive brystkreftceller utrykker hittil ukjente markører som kontrollerer tiltrekning av nerver til primærsvulsten, og at denne tiltrekningen forårsaker endringer i en undergruppe av brystkreftceller som fremmer spredning til hjernen.

Recent data indicate that nerves might play an active role in the initiation and progress of cancer. In the breast, research by us and others has demonstrated that enhanced innervation is associated with more aggressive tumors, such as the triple negative subtype (TNBC) supporting the formation of a neurogenic niche in primary tumors. However, the detailed clinical relevance of this phenomenon, and the mechanisms by which nerves are attracted to breast tumors and how breast cancer-nerve interaction promotes aggressive tumor features, remain unexplored. Moreover, we lack good experimental models for breast cancer innervation in a human setting. 

TNBCs with a basal-like phenotype are also prone to metastasize to the brain, the most neurogenic niche in the body, but the preference for the brain as a metastatic site is not understood, neither are the phenotypic alterations that breast cancer cells undergo in brain tissue. Here, we launch a new concept - epithelial-to-neural transition (ENT) – linking cancer cell plasticity and nerve involvement in primary and brain metastatic breast cancer. We suggest that aggressive breast cancer cells express yet unknown markers that control attraction of nerves at the primary site, and that some breast cancer cells even transform by acquiring neural-like properties and spread to the brain. Epithelial-to-neural transition will be investigated both clinically and experimentally in primary and brain metastatic breast cancer by combining large clinical cohorts, spatial omics technology, and stem cell methods to establish cutting-edge models. 

This project has the potential to change the way we view neural elements in breast cancer and provide the field with new clinical relevance, models and technologies to study them.

When breast cancer hits a nerve
- Neural involvement as a hallmark of tumor progression

Immunforsvaret vårt gir oss et naturlig forsvar mot kreftutvikling. Naturlige dreperceller, også kalt Natural Killer (NK) celler, er en del av immunforsvaret og er spesialiserte på å søke ut og tilintetgjøre kreftceller. Kreftceller kan unngå immunforsvaret, og vil når det skjer vokse til en svulst. NK-cellene er ikke gode til å trenge inn i svulsten, og kan dermed ikke ta livet av kreftcellene. NK-cellenes våpen er giftstoffer som sprøytes inn i kreftcellene når de får direkte kontakt. I tillegg kan NK-cellene produsere små missiler som inneholder gift. Disse missilene slippes vanligvis løs når NK-cellene møter en kreftcelle. På laboratoriet kan vi dyrke NK-celler, og få dem til å slippe ut missilene sine. Vi samler opp missilene, og kan så bruke disse til å drepe kreftcellene. Missilene er veldig små, og har bedre evne til å trenge inn i en svulst. Med dette prosjektet ønsker vi å forstå hvordan missilene lages i NK-cellene, og å bedre forstå hvordan de søker opp og dreper kreftcellene. Vi håper at vi med dette prosjektet vil legge grunnlaget for en fremtidig kreftterapi.

With this project, we will build the basis for developing NK-cell derived extracellular vesicles (NK-EVs) as a new cancer therapeutics. NK cells and CAR-NK cells are already being exploited in therapies against hematological malignancies and solid tumors. With NK-EVs we will leverage on the combined power of the killing capacity of NK cells with that of the advantageous aspects of EVs as natural carriers of biomolecules and tissue penetration. We and others have demonstrated that NK-EVs induce apoptosis of a wide range of cancer cells in vitro, and a few studies have also shown efficacy in vivo. EVs are emerging as a new therapeutic avenue in several disease contexts, but the field needs to address and solve critical bottlenecks to allow their exploitation. This proposal will address two major knowledge needs, which is 1) to determine the mechanism of action of NK-EVs, and 2) to understand the heterogeneity of the NK-EV secretome to define the EV subset inducing cytotoxicity. To address these needs, we will perform CRISPR screens in two cancer cell lines to discover proteins that are necessary for mediating the effects of NK-EVs, further we will define the precise mechanism of action of how NK-EVs deliver their cytolytic cargo, and finally utilize single-EV technologies to dissect the EV secretome form NK cells released under different stimulatory conditions. Results from this study will be used to design production protocols and relevant potency assays which is a prerequisite for developing NK-EVs into a therapeutic product.

Cytotoxic activity of NK cell-derived extracellular vesicles against cancer cells.

Økonomisk ulikhet øker i Norge og andre høyinntektsland, mens innvandring også er med å endre samfunnets demografiske og sosioøkonomiske struktur. I kjølevannet av økende økonomiske og etniske forskjeller, er det bekymringsfullt at ulike dimensjoner av ulikhet blir stadig mer vedvarende på tvers av generasjoner. Å fremskaffe kunnskap om i hvilken grad ulikhet overføres innenfor familier og bredere sosial kontekster, vil kunne si noe om hvilke muligheter man har senere i livet. Til tross for mye forskning på intergenerasjonell mobilitet for utdanning og arbeid, har det vært lite forskning på betydningen av helse i overføringen av sosioøkonomisk status fra foreldre til barn.  
I  HEALTHMOBILITY ønsker vi å studere (1) i hvilken grad helsestatus overføres gjennom generasjoner og sammenhengen mellom helse og sosioøkonomisk mobilitet, (2) den kausale effekten av helseforskjeller tidlig i livet og i ungdomsårene på voksne prestasjoner og sosial ekskludering, (3) i hvilken grad de ovennevnte prosessene varierer mellom barn av innvandrerforeldre og de uten innvandringsbakgrunn, og, (4) hvordan forholdet mellom sosioøkonomisk status og helse har utviklet seg historisk—ved å studere langsiktige trender som strekker seg over mer enn 50 år. Prosjektets bidrag vil være å undersøke betydningen av både foreldre og barns helse som en dimensjon av intergenerasjonell mobilitet, sosial ekskludering, og livsjanser gjennom generasjoner.

Economic inequality is on the rise in Norway and other high-income countries, while large-scale immigration is also changing the demographic and socioeconomic structure of these societies. In the wake of widening economic disparities and ethnic inequality, there is growing concern among social scientists and policy makers that various dimensions of inequality are becoming increasingly persistent across generations. Knowing to what extent inequality is perpetuated within families and within broader social contexts is crucial since most would agree that opportunities in life should not be determined by which family a child is born into. Despite a vast literature on intergenerational mobility and children’s prospects for moving up the socioeconomic ladder, there is little research on the intergenerational transmission of health status and its role in the transmission of socioeconomic status from parents to children. This is unfortunate, as health is increasingly acknowledged as an essential part of individuals’ human capital, with important consequences for individuals outcomes in education and the labor market. 
In HEALTHMOBILITY we aim to study to what extent (1) health status is passed down through generations and its relation to socioeconomic mobility, (2) the causal impact of early-life health disparities on adult attainments, (3) to what extent these processes vary between children of immigrant and native parents, and (4) how the relationship between socioeconomic status and health status have evolved historically. Our aim is to unpack how mechanisms related to intergenerational transmission of health inequality contributes to socioeconomic and ethnic disparities in educational and labor market attainments. We will use Norwegian data from population-wide administrative registers and large-scale surveys, with detailed information on health service use, self-reported measures of health, and key socioeconomic and demographic characteristics to address these issues

Socioeconomic and Ethnic Inequality in Health and Intergenerational Mobility (HEALTHMOBILITY)

Antimikrobiell resistens (AMR) er en alvorlig trussel mot folkehelsa som er spådd å bli verre i fremtiden. En av de vanligste metodene som bakterier bruker for å kunne stå imot antibiotika, er å skaffe resistensgener. Disse sitter ofte på noen DNA-deler som heter plasmider. Plasmider som bærer resistensgener er vanligere i kliniske miljøer enn samfunnet ellers, og det å forstå hvorfor vi har denne forskjellen er svært viktig for å forstå hvordan resistente bakterier sprer seg. Men plasmider utvikler seg raskt, og kan spre seg mellom forskjellige bakteriestammer. Derfor er det vanskelig for oss å klassifisere og overvåke dem. I PEAK skal vi benytte oss av nye sekvenseringsteknologier og utvikle nye metoder for å forske på hvordan plasmider utvikler seg og sprer seg, med fokus på den viktige sykdomsfremkallende bakterien Klebsiella pneumoniae. Vi skal utvikle nye metoder for å klassifisere plasmider og analysere de genetiske forskjellene mellom plasmidgrupper. Deretter skal vi bruke disse plasmidgruppene til å forske på hvordan plasmider sprer seg mellom forskjellige miljøer og typer Klebsiella. Så skal vi utføre detaljerte analyser av de genetiske endringene som driver utviklingen av plasmider. Målet er å bruke de nye metodene og kunnskapen til å forbedre overvåkning, både av AMR Klebsiella pneumoniae og andre bakteriestammer.

Antimicrobial resistance (AMR) is a global threat to human health which is predicted to increase in the future. One of the most common ways that bacteria evolve resistance to antibiotics is by acquiring AMR genes; these are often carried on small pieces of DNA called plasmids. Understanding the mechanisms and conditions that promote AMR dissemination via plasmids is critical, but several knowledge gaps remain. AMR is unevenly distributed among environments, whilst the highest levels of AMR are typically found in clinical environments, the risk of AMR acquisition from environmental and animal settings remains less clear. Plasmids are important vectors for the transmission of AMR between environments, but plasmid evolution is complex, and lack of appropriate data and methods has to date largely precluded high-resolution study and surveillance of plasmids in most major pathogens.

In PEAK, we will use two newly generated long-read sequencing datasets to study the evolution and transmission of plasmids and AMR genes in Klebsiella. By combining the datasets, consisting of 1594 isolates from diverse one-health sources, we will establish a unique collection of hybrid assemblies, including thousands of complete plasmids. Next, we will develop novel methods to quantify the genetic structure and diversity of plasmids. By combining this information with genetic variation in the isolate chromosomes and metadata, we will then perform phylogenetic and association analyses to disentangle AMR distributions among environments. This will enable us to identify high-risk environments for AMR transmission, followed by detailed evolutionary analyses to gain insight into the tempo and mode of plasmid evolution, and how chromosomes coevolve with plasmids.

The overarching aims of PEAK are to uncover the drivers and mechanisms of the acquisition and maintenance of AMR, with the ultimate goal of enabling use of this knowledge to design interventions to combat the spread of AMR in the future.

PEAK: Plasmid Evolution and Antimicrobial resistance in Klebsiella pneumoniae

Verifying the therapeutic potential of newly discovered siRNA drug candidates for treating acute leukemia.

Midlene fra VM-Vareproduksjon og materialforedling fordelt på år

Midlene fra VM-Vareproduksjon og materialforedling fordelt på fylker

Midlene fra VM-Vareproduksjon og materialforedling fordelt på fagområde

Shaped castings of light metal (Stykkstøping av lettmetall)

The 28th Organic Chemistry Winter Meeting

The 27th Organic Winter Meeting will take place January 12th-15th 2012 at Thon Hotel
Skeikampen. This conference is the national meeting in organic chemistry in
Norway, and it is held under the umbrella of the Division of Organic Chemistry of the
Norwegia n Chemical Society.
Since the initiation of the conference, we have each year invited 3-4 foreign chemists,
internationally recognized in their fields of research. Due to financial support from the
Norwegian Research Council over the years it has been pos sible to maintain this tradition
without having to charge a considerable conference fee. This has been absolutely instrumental
to keep up the numbers of participants in times with little money at Norwegian universities for
conference participation.

Organisk Kjemisk Vintermøte, Skeikampen 12.-15. januar 2012

Fischer-Tropsch synthesis is one of the key processes in natural gas conversion. Enormous efforts have been devoted to increase C5+ selectivity.  However, a detailed understanding of elementary steps leading to chain growth is still missing. The project a ddresses identification of important factors controlling chain growth in Fischer-Tropsch synthesis, through detailed study of steady-state transient kinetic analysis of elementary steps on Co and Co alloy surfaces. The catalyst will be synthesized in a co ntrolled manner, and characterized in detail to determine the properties. Transient responses of C2-C7 will be analyzed and modeled and the kinetic parameters responsible for chain growth will be correlated to the electronic properties of Co and Co alloy  surfaces.

Fundamental understanding of the controlling factor for the C5+ selectivity for Co/CNF catalysts in Fischer Tropsch synthesis

Epidemiological studies have linked fat fish consumption to lower rates of several diseases such as cancer and Alzheimer's disease. Fish contains high levels of omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid and docosahexaenoic  acid. Recently, the potential efficacy of omega-3 PUFAs in the inhibition of tumor growth was reported, most likely by reducing the blood and nutrient flow to the cancer tumors. An attractive anti-cancer strategy could be accomplished if the flow of oxyge n and nutrients could be reduced. This would eventually starve the tumor. One lipid-based molecule derived from an omega-3 polyunsaturated fatty acid that was reported to reduce the flow of oxygen and nutrients is resolvin. We will in this research projec t make resolvin and further study its ability to reduce the flow of oxygen and nutrients to cancer cells. These studies should provide useful information towards potentially new anti-cancer agents based on the chemical structure of resolvin.

Synthesis of resolvin D1 and analogs as potential anti-angiogenetic agents

Fundamental study down to the atomic level is crucial for improving our understanding of catalysts and enhancing our ability for their rational design. The present project deals with exploring advanced TEM techniques such as aberration corrected microscop y and environmental TEM for imaging of composition and bonding. Elemental and valence sensitive imaging of Co nanoparticles and Pt based core-shell structured nanoparticles will be obtained by STEM combined electron diffraction and electron energy loss sp ectroscopy. The strain of the nanoparticles will be studied as a function of particle size and different supports in terms of catalytic performance in different reactions. The thickness and uniformity of the shell of core-shell structured nanoparticles wi ll be studied by atomic imaging. The interface between core and shell layers will be studied by aberration corrected microscopy. The project will enhance the cooperation with world leading groups at DTU and Lehigh University.

Fundamental understanding of catalyst nanoparticles by atomic scale chemical imaging

Aminophosphonates are interesting compounds due to their analogy with amino acids and their derived peptides. They could interfere in biological mechanisms through their hydroxyphosphonyl group approximating the enzymatic reactive tetrahedral intermediate . We aim at creating a new basis for the investigation of aminophosphonates as amino acid mimics. In the research focus is the practical, efficient and enantioselective methodologies for the synthesis of aminophosphonates. Chiral ammonium salts that are p hase-transfer catalysts will be evaluated in preparation of such aminophosphonates. Phosphapeptides will be prepared by incorporating an aminophosphonate residue in short peptides, and will be studied using NMR together with computational chemistry as too ls to gain insight into changes in their conformations, dynamics and type of aggregates.

Design and synthesis of chiral aminophosphonates: from biomimetic catalysis to phosphapeptides

Gold catalysis of organic reactions has  become a rapidly expanding field in recent years after being neglected by organic chemists for a long time. Gold catalysts react in very selective ways and may give access to highly complex molecules. The present p roject describes the continued investigations of our recently discovered new gold catalysed mono- and tandem cyclisation reactions, covering mechanistic studies and modified substrates, such as vinylesters/-amides, indoles, alkynesulfoxides, as well as st eroselective gold catalysed reactions.

NHC (N-Heterocyclic Carbene) compounds are electron-rich N,N-disubstituted imidazol-2-ylidenes developed the last decade due to their attractive properties. In particular, they play a favourable role in transition m etal catalyzed reactions, replacing the traditional phosphine ligands. We will design and prepare a number of new chiral NHC ligands, based on suitable approaches for such syntheses. The ability of the new NHC ligands to afford chiral induction in organoc atalytic transformations will be studied.

A collaboration with a research group at the University of Hamburg and SINTEF Biotechnology, Trondheim, has been established.

Gold catalysis and new chiral NHC compounds.

Inntak av omega-3-fettsyrer som eicosapentaensyre (EPA) og docosaheksaensyre (DHA) har i flere studier vist å gi positive helseeffekter. Disse omega-3-fettsyrene finnes i tran og fet fisk. De eksakte molekylære årsakene til disse positive helseeffektene e r ennå ikke klarlagt. 

Ny forskning utført av gruppen til professor Charles N. Serhan, Harvard Medical School, har vist at EPA og DHA omdannes til hydroksylerte derivater i mennesker og dyr. Disse hydroksylerte omega-3-fettsyrederivatene har i musemode ller og i kliniske studier vist meget gunstige og potente effekter i demping av inflammasjon. Inflammasjon gir opphav til en rekke sykdommer. Effektene fra de hydroksylerte derivatene er mye sterkere sammenlignet med effektene man ser fra både EPA og DHA.  Særlig interessant er observasjoner som viser at de hydroksylerte derivatene hindrer utviklingen av nevrodegenerative sykdommer som Parkinson og Alzheimers sykdom. Protectin D1 er et eksempel på et hydroksylert omega-3-fettsyrederivat. Protectin D1 danne s i nano- til mikrogrammengder i levende systemer når inflammasjon oppstår. Ukontrollerte inflammasjonsprosesser kan føre til nevrodegenerative sykdommer. Syntetisk organisk kjemi blir da nødvendig for å sikre nok mengder av protectin D1 for biologiske st udier og ikke minst kliniske studier. Protectin D1 er for tiden i kliniske studier som et mulig nytt legemiddel mot Parkinson sykdom.

I dette KOSK-II finansierte prosjektet har protectin D1 blitt fremstilt ved Farmasøytisk institutt, Universitetet i Os lo. Protectin D1 kan eksistere i 256 mulige tredimensjonale strukturformer. Essensielt for de gunstige biologiske effektene som protectin D1  viser, er at den tredimensjonale strukturen må være lik den naturen lager; avvik fra denne gir en drastisk reduks jon i biologisk aktivitet. I dette prosjektet er kun den korrekte strukturen av protectin D1 fremstilt. Dette har blitt bekreftet ved å sammenligne autentisk protectin D1 isolert fra levende materiale med syntetisk protectin D1 fremstilt i Oslo.

Videre  har også flere analoger av protectin D1, som i museforsøk viser de samme gunstige egenskapene med å dempe inflammasjon, blitt fremstilt som del av dette prosjektet. Dette har gitt mye nyttig informasjon som kan anvendes i utviklingen av nye potensielle l egemidler mot nevrodegenerative sykdommer, herunder Parkinson og Alzheimers sykdom. 

Det eksperimentelle organisk syntetiske arbeidet har blitt utført ved Farmasøytisk institutt, legemiddelkjemi, mens biologisk testing i musemodeller har blitt utført v ed Harvard Medical School, Boston, i gruppen til professor Charles N. Serhan. Samarbeidet mellom disse to gruppene vil nå fortsette.

I lang tid har inntak av tran og fet fisk vært ansett som helsebringende. Først nå har kunnskapen om de molekylære årsa kene bak de helsebringende effektene, begynt å bli klarlagt. Det er spennende at et norsk forskningsmiljø bidrar til denne nye forskningen og kunnskapsbasen, spesielt siden Norge har en lang og sterk tradisjon innen fiske og fiskeforedling.


Epidemiological studies have linked fat fish consumption to lower rates of neurological diseases such as Alzheimer's disease. Fish contains high levels of omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Recently  several lines of evidence indicate that docosahexaenoic acid acts in the brain via anti-apoptotic, neurotrophic pathways and anti-inflammatory pathways. In the body and especially the brain, docosahexaenoic acid is converted to a class of molecules terme d protectins that have anti-inflammatory properties. The most potent compound was protectin D1. In this research proposal we will prepare this polyunsaturated fatty acid derived natural product named protectin D1, but also some of its analogs. The natural  product and its analogs will be submitted to molecular modelling and biological testing, and the biological testing will inform us if protectin D1 and its analog may be potential drugs against neurological diseases, for example Alzheimer's disease. With  full knowledge of the physiological role the protectins have on neuroinflammation, control of a number of maladies, such as Alzheimer's disease, disease may be possible.

Synthesis, molecular modelling and biological evaluation of protectin D1 and analogs

Aluminosilicate zeolites are solid acids that may act as catalysts for various reactions, such as the conversion of methanol to light alkenes. Recent NMR results obtained in a joint project between UiO and the group of Prof. Francis Taulelle in Versailles , France, give new insight into the local environment at the active sites in zeolites. A longstanding issue in this area of research is whether aluminium is randomly distributed among the different framework sites, if certain positions are preferentially  occupied, or if ordering may occur. Advanced solid-state NMR results indicate that framework T-atoms may show considerable mobility during calcination and also during the catalytic reaction. Further, aluminium atom pairing appears to take place to a large  extent. The postdoc for whom we apply for funding will perform quantum chemical calculations to elucidate the relative stabilities of various T-atom configurations and crystal defects. Further, he or she will attempt to determine the mechanism(s) of T-at om diffusion in the material. Finally, NMR spectra will be computed and compared to experimental results to yield far more reliable characterization than what would be available from experiment or theory alone.

Quantum modelling studies of local coordination of T-atoms in zeolites

Halogenation reactions are of great practical importance within the field of synthetic organic chemistry, and halogenated molecules can have highly advantageous biological properties. For instance, fluorinated and chlorinated molecules are frequently enco untered both in drug design and among naturally occurring pharmaceutically active compounds. Our research group has recently developed a new, green method for generation of electrophilic transition-metal carbenoid precursors containing halogens. Electroph ilic transition-metal carbenoids are valuable intermediates in organic synthesis, used for example in the preparation of various natural products and pharmaceuticals agents. We have explored the utilisation of the halogenated carbenoids as a novel way of  selectively introducing halogens. The aim of this project is to generate a variety of new halogenated and boronated carbenoid precursors, and to develop methods for their application in carbon-carbon bond forming reactions. This will broaden the range of  easily accessible halogenated and boronated molecular building blocks. An additional goal is to develop methods for the use of these building blocks in further transformations. The expected findings of this project will be useful tools in organic chemistr y.

Novel carbenoid chemistry

Gold catalysis of organic reactions has  become a rapidly expanding field in recent 5 years after being neglected by organic chemists for a long time. Gold complexes are less oxophilic than other common Lewis acids, but they are highly reactive as Lewis a cids towards carbon-carbon multiple bonds. Gold catalysts can therefore react in a very selective way and give access to highly complex molecules. The present project describes the investigation of new gold catalysed cyclisation reactions of diynes.

NHC  (N-Heterocyclic Carbene) ligands are electron-rich N,N-disubstituted imidazol-2-ylidenes developed the last decade due to their attractive properties. In particular, they play a favourable role in transition metal catalyzed reactions, replacing the tradit ional phosphine ligands. We will design and prepare a number of new chiral NHC ligands, based on suitable approaches for such syntheses.

A collaboration with a research group at the Universities of Hamburg has been established.

Gold catalysis and new chiral NHC ligands.

Dessa vintermöten anordnas varje år av Norsk Kjemisk Selskap. Ansvaret för arrangangen roterar mella lärosätena i Norge och vid vilka en huvudansvarig utses.För år 2010 är det undertecknad vid Univeritetet i Ttomsø som har fått detta ansvar. Med denna ans ökan begärs ett finansiellt stöd från NFR för att täcka kostnaderna för de inviterade fördragshållarna.

Det 25. Organisk Kjemiske Vintermöte

Norsk katalysesymposium arrangeres i Trondheim 30.11. - 1.12.2009. Vertskap for arrangementet er katalysegruppa ved NTNU. Konferansen samler en stor andel av de som er aktive innen katalyse i Norge innen akademia og instituttsektoren, samt sentrale aktøre r fra industrien. Symposiumet fungerer også som samling for SFI-inGAP og som årsmøte for programmet KOSK-II.

Norsk katalysesymposium 2009

Kobolt baserte Fischer-Tropsch katalysatorer får høyere aktivitet dersom de promoteres med en liten mengde av et annet metall. Det kan være edelmetaller som Pt, Re, men ogs rimeligere alternativer som Ni. Dette prosjektet søker å finne ut mer om interaksjonene mellom kobolt og promotoren i katalysatorene. En serie kobolt-baserte katyalysatorer for Fischer-Tropsch syntesen promotert med Ni eller Re har blitt fremstilt. Ulike former av aluminiumoksid har blitt benyttet som bærermateriale for katalysatorene: Gamma-alumina,  alfa-alumina og også ordna mesoporøs alumina har blitt benyttet. 
Ordna mesoporøs alumina med sitt veldefinerte poresystem er et veldig interessant modellsystem. Det gir oss mulighet til å ekskludere effektene av porestørrelse på katalysatoregenskapene. Karakterisering av katalysatorene er utført ved NTNU ved hjelp av Grazing Incidence Small Angle X-ray Scattering (GISAXS) og elektronmikroskopi (Scanning Electron Microscopy (SEM)).
De katalytiske egenskapene til Re og Ni promoterte Co-FT katalystatorer har blitt undersøkt in situ med røntgen absorpsjonsspektroskopi (XAS) hvor vi også anvender fasemodulasjon for å øke overflatefølsomheten (modulation excitation spectroscopy (MES)). Det eksperimentelle oppsettet har blitt komplettert og allerede tatt i bruk ved SNBL, ESRF. Forskjellene i elektronisk struktur mellom promoterte og upromoterte katalysatorer har i tillegg blitt undersøkt med RIXS og HERFD XAS ved W1 strålelinjen ved HASYLAB, Hamburg. 
Prosjektet har blitt ledet av Professor Magnus Rønning, Institutt for kjemisk prosessteknologi, NTNU. Ph.d. student Georg Voss ble uteksaminert ph.d. fra NTNU I august 2014.


Co-Re is often the main active constituents in natural gas based Fischer-Tropsch synthesis. In order to reduce the amount of non-reduced cobalt, a small amount of Re can be introduced into the catalyst system. It is generally accepted that rhenium mainly  catalyses the reduction of cobalt species interacting with the support. The nature and location of the promoter is also unclear, especially at reaction conditions. Re supported on alumina can be present in a large variety of oxidation states. A large numb er of studies have used XAS, Raman and IR spectroscopies to study the nature of Re species in such catalysts. However, all studies are based on Re LIII edge XAS and reduced samples at ambient pressures. Raman studies employ lasers in the visible region an d most frequently ex situ. Some studies are performed ex situ on used catalysts, but mostly only in the reduced state. That is, relatively far away from industrial Fischer-Tropsch conditions. We therefore propose a project where the experimental condition s are more realistic and where we use recent advances in instrumentation to extend the range of information about this very important industrial catalyst system. e have recently invested in a combined Raman-IR instrument equipped with both a near-IR and a  UV laser. Furthermore, the instrument is equipped with fibre optics and a dedicated in situ catalyst cell. Hence, we want to take advantage of the capabilities of this instrument to study the Re species on Co-Re FT catalysts. There is an urgent need for  scientific personnel that can dedicate time to explore the full capabilities of the instrument. This proposal will make it possible to fully utilize the potential of these instruments on catalyst systems. This proposal is also aiming at exploiting the cur rent upgrade of the Swiss-Norwegian Beamline B-station from a standard powder X-ray diffraction (XRD) and absorption spectroscopy (XAS) beamline to a versatile state-of-the-art beamline for in situ studies

The state of rhenium in cobalt-rhenium Fischer-Tropsch catalysts

The Catalysis group at the Department of Chemistry, University of Oslo and the Department of Hydrocarbon Process Chemistry at SINTEF Materials and Chemistry have been collaborating fruitfully for decades, and during the last 10 years they have exploited t he synergy between experimental and computational methods with great success. This project involves one new PhD student. The PhD candidate will be dependent on interaction with scientists at both UiO and SINTEF, due to the methodologically advanced nature  of the project.

Aluminosilicate zeolites and silicoaluminophophate SAPO-type materials are solid acids that may act as catalysts for the conversion of methanol to light alkenes. Recent NMR results obtained in joint project between UiO and the group of P rof. Francis Taulelle in Versailles, France give new insight into the local environment at the active sites in zeolites. A long withstanding issue within the research on these materials is whether or not Al (or Si for the SAPOs) is randomly distributed am ong the various framework sites, if certain positions are preferentially occupied, or if ordering may occur. Advanced solid state NMR indicates that the mobility of framework T-atom during calcination of the catalytic reaction is substantial and that Al p airing takes place to a large extent. Within the current project, the PhD candidate will perform synthesis of microporous materials of the CHA structure and submit these to extensive characterization using solid state NMR utilizing a new instrument at SIN TEF, as well as other characterization techniques.

Advanced Characterisation of Local Coordination of T-atoms in Microporous Materials with CHA Topology

Nanocrystals with well controlled size, shape and surface composition provides excellent opportunities not only in fundamental study of heterogeneous catalysis but also for improving existing catalysts or design new catalysts for chemical processes. Porpa ne dehydrogenation is a conventional chemical process to meet the increasing demand of olefins. Pt or Pt-Sn is the typical catalysts for the reaction. The present work will explore the progresses in nanotechnology to prepare Pt and Pt-Sn nanocrystals with  well controlled size and shape to address the structure-property-performance relationship, which will be achieved by combined advanced characterizations and detailed catalytic tests in TEOM reactor. Selectivity to coke and methane will be minimized by ra tional catalyst design. In addition, interaction between Pt or Pt-Sn nanocrystals and new support namely SiC nanofibers will also be addressed to improve stability for industrial applications.

Engineering of Pt nanoparticles in Propane Dehydrogenation

Telescope reactions:
Assume that a three-step reaction is to be optimised: Lay out a statistical design to map the first step. Run the experiments an determine the responses. The response matrix Y=[y1 y2 ....ur] summarises the results. A principal compone nt model will determine the number of independent events yielding Y, i.e. the number of independent reactions yielding the desired product and byproducts.  By fitting regression models to the PCA score vectors it is possible to identify those variables th at are necessary to control for favouring the desired reaction, and which variable to control to suppress the parasite reactions. The important variables from the first reaction step are now added as extra design variables for the next step. The outcome o f the first steps is the input for the second step, By perturbing teh variables of the first step we introduce variation of the input of the second step. The evaluation as depicted above will now reveal the important variable of the first two steps. The p rocedure in then iterated for the subsequent step. This will give quantitative models for multi-step reactions.

Orthogonal experiments:
With new synthetic reaction it is important to determine as early as possible if the reaction can be developed into a  new synthetic method. A new method for designing such explorative experiments is developed. The feature is that the search space defined by variable settings, interactions between variables can be explored by peeling of one dimension at a time of the sear ch space. The model space is factored by singular value decomposition (SVD) and the experiments that are most parallel to the singular vectors are selected. This yields a A-Optimal design. These principles are being tested with new reactions of synthons f rom small brominated unsaturated ketones.

Design and optimisation in organic synthesis:Optimisation of telscope reactions and methodologies base on orthogonal experiments

Production of synthesis gas (carbon monoxide and hydrogen) is a process of major importance for chemical upgrading of natural gas. In this process, a catalyst consisting of metal clusters supported on an oxide surface is used. The project's main challenge  will be to elucidate the role of strong metal/support interactions (SMSI) in the reforming of light alkanes on oxide-supported nickel catalysts. This is a demanding task, requiring the use of new methods. Specifically, we will use computational methods b ased on quantum chemical and band structure calculations. Of particular interest are the following questions:

A. Does CO2 preferentially chemisorb on the metal or the support?
B. What is the fate of CO2 immediately after chemisorption? Surface diffusion or dissociation or both?
C. Spillover: How may CO2 diffuse between metal and support? 
D. Reactions at the metal-support interface: Will CO2 simply spill over to the metal and then dissociate, or is CO2 dissociation facilitated at the metal-support interf ace?

Strong emphasis will be placed on the interface between metal and oxide; the diffusion of CO2 past the interface, and reactions taking place at the interface. Elucidation will be achieved by considering and comparing the reaction and activation ener gies for a number of different elementary steps. The results from the project will put us in a position to design better catalysts on a more rational basis.

Quantum chemical modelling of metal-support interactions in metal-based catalysts

It has been found that the CNFs are promising as supports to achieve high activity and selectivity due to their mesoporous structure, high mechanical strengths, high surface areas. More importantly, it was found that the activity and selectivity of F-T ca talysts depends significantly on the Co crystal size and the graphite orientation of the CNFs. The present work will prepare Co nanoparticles with well controlled size, shape and composition supported on carbon nanofibers with different graphite sheet ori entations in terms of the axis of fibers. The sample will be tested in both low and high pressures. Different characterization techniques will be used to study the interaction between CNF and Co, their effect on the Co properties including adsorption prop erties of CO, H2 and H2O. The research will focus on identification of controlling factors to control the activity and selectivity of Co catalyst in F-T synthesis. The experimental results and the results from DFT calculations will be implemented in a mic rokinetic model, which can be further used as a tool for rational catalyst design.

Fundamental understanding of novel Co catalysts on carbon nanofibers in F-T synthesis

Cancer is an important public health concern around the world. Chemotherapy is no doubt one of the most successful ways in which cancer can be treated. For years, chemotherapy has been indiscriminate warfare by using chemotherapeutic agents that are toxic  to both normal and cancer cells. In this project we will design, prepare and evaluate molecules that are benign towards normal cells. 

Each individual has different levels of proteins in the body. If a personalized cancer treatment would become availabl e, this should reduce the need for different chemotherapeutic agents before finding one agent that works. This should offer advantages such as reduced treatment time, costs for society and reduce the many side-effects that cancer patients suffer. 

In thi s research project we develop molecules that should have potential as personalized cancer therapy. These small organic molecules activate the protein caspase-3. This protein is generated after activation of procaspase-3. The conversion of procaspase-3 to caspase-3 results in the generation of an executioner protein that induces cell death for the cancer cells. From a chemotherapeutic perspective, it is interesting and noteworthy that cells from certain types of cancerous tissues, such as colon, lung, mela noma, renal and breast cancers, contain elevated levels of procaspase-3. Hence, by measuring the level of procaspase-3 in patients before chemotherapy is initiated, treatment using a procaspase-3 activating drug will be given only to those patients that h ave elevated levels of procaspase-3. Hence, a personalized cancer strategy is achieved.

Synthesis of novel activators for procaspase-3: an approach to a personalised cancer treatment

The Tilset group has made important contributions towards selective C-H activation and functionalization at platinum complexes in solution and, recently, in development of novel Pt-containing metal-organic frameworks that may be of interest for catalytic applications.
One drawback (this applies to homogeneous systems and even more so to heterogeneous MOF systems) of the Pt complexes studied so far is that C-H activation at Pt(II) complexes requires electrophilic activation of synthesized complexes, usuall y by protonolysis, to generate cationic C-H activating species.
In this project, we seek to avoid the need for electrophilic activation by designing new cyclometallated heteroaromatic ligand systems. These ligands are formally monoanionic and the C-H acti vating species will be neutral. Closely related ligands may be used for homogeneous studies and for MOF synthesis.
The approach of using monoanionic ligands will have positive consequences for the study of C-H activation in solution, and will significantl y aid our efforts towards constructing catalytically active MOFs.

C-H Activation reactions at neutral cyclometalated Pt complexes

Nature is a rich source of bioactive compounds and potential drugs. The so-called secondary metabolites are structures involved in interaction between organisms, for instance chemical defense. Studies of such metabolites have led to the discovery of many life-saving drugs, including antibiotics, immunosuppressant and antineoplastic agents. The last 50 years there has been an increasing interest for marine natural products as potential drugs and molecular tools, since an enormous chemical and biological di versity are found among metabolites from marine species. However, most bioactive marine products can only be isolated in very minute amounts, and bioprospecting must be combined with state of the art organic synthesis in order to explore the true potentia l of these chemically complex structures. Organic synthesis also open up the possibilities for preparation of marine natural product analogs which may be easier to synthesize, and which may also possess improved properties regarding bioactivity, bioavaila bility etc. 
Asmarines have been isolated from marine sponges (Raspailia sp). Currently 11 asmarines are known, and asmarines A and B are reported to possess significant cytotoxic activity against various human cancer cell lines. This project is aiming at  the first total synthesis of one or more asmarines, even though this overall goal may not be reached within this project period. Compounds synthesized will be evaluated as potential antimicrobials (against pathogenic bacteria, incl. mycobacteria, fungi a nd protozoa), and potential anti-cancer compounds. While working towards a total synthesis of one ore more asmarines, several analogs or model substances will be synthesized. Their antimicrobial and cytotoxic activity will be studied. This will lead to in creased knowledge regarding structure-activity relationships (SAR) for asmarines and analogs. In due course, potential antimicrobial or anti-cancer drugs with optimized structures compared to the parent natural pro

Synthetic studies directed towards asmarines and other purines with fused heterocyclic systems

This project will focus on the development of much needed novel inhibitors of the aspartic proteases related to HIV/AIDS and Alzheimers disease. In order to pursue these goals, the project seeks to establish a strong research group in medicinal chemistry at the Centre for Pharmacy at the University of Bergen. This research group will be lead by Dr. Bengt Erik Haug, and its establishement will be facilitated through national and international collaboration with highly esteemed scientist.

The project will involve chemical synthesis of novel compounds that have been designed based on known inhibitors of aspartic proteases. These compounds will be tested for their inhibiton of key enzymes that are known targets for the treatments of HIV/AIDS and Alzheimers d isease. Based on the results obtained, new sets of compounds will be prepared and tested.

We plan to use molecular modeling as an integrated part of the project to facilitate the design of new sets of inhibitor based on the structures of the target prote ases and identified inhibitors.
Co-crystallization of identified inhibitors with their respective protease targets for the purpose of  solving their three-dimensional structures using X-ray crystallographic methods will also be pursued.

Design and synthesis of novel aspartic protease inhibitors.

The production of valuable chemicals via selective functionalization of saturated and unsaturated hydrocarbons is a major challenge in the field of contemporary organometallic chemistry.  A particularly attractive substrate is methane which has previously  been successfully C-H bond activated by electrophilic late transition organometallics under harsh conditions.  Highly electron-deficient donor solvent-free metallocene complexes of the rare-earth elements were also shown to activate methane via non-oxida tive mechanisms (e.g., sigma bond methathesis).  Such activation scenarios were successfully exploited for catalytic (stereoselective) hydrosilylation reactions.  The goal of this project is to sound out the C-H bond activation capability of various rare- earth metal tetramethylaluminate complexes which have been recently synthesized in our group.  Main emphasis will be put on studying monocyclopentadienyl and postmetallocene derivatives with respect to in situ generation of reactive Ln-alkyl bonds and lab eling experiments.  Consideration is given to aliphatic, olefinic, and aromatic substrates including donor-functionalized molecules such as pyridine.

Rare-Earth Metal-Promoted C-H Bond Activation

Radiation treatment of head and neck cancer must be suspended due to Candida infection in the mouth and throat. This is just an example showing the need for new treatment of fungal infections. The present project addresses these issues by proposing to ide ntify pharmacophores for antimicrobial action towards these infections. The research will follow the lines our group already has utilised for making extremely small antimicrobial peptides, compounds that are now in preclinical evaluation for treatment of infections caused by multiresistant Stapylococcus aureus by a pharmaceutical company. The proposal calls for the development of novel synthetic methods for generation of focussed libraries, utilisation of high throughput screening facilities and creation of quantitative structure-activity relationships (QSAR) in a full drug design cyclus. The synthetic work and the QSAR will be undertaken in my research group in cooperation with the Micropep I staff and internal collaborators, while the biological testing  will be undertaken by a network of highly recognized research partners. The project is also supported by Lytix Biopharma AS.

MICROPEP II - Design and synthesis of antimicrobial peptides targeted against pathogenic fungi.

A number of substituted 3-nitropyridines are now easily available by a new nitration method, and some of these derivatives are suitable substrates for the preparation of a series of bis-heterocycles. We will investigate the chemistry of nitropyridyl deriv atives further and propose to utilise 3-nitropyridyl substrates for the formation of a series of heterocyclic compounds, many of which are present in pharmaceuticals. We want to study:
- the synthesis of beta-carboline analogues and furo-/thieno-azacinnol ines,
- cycloaddition reactions with benzyne and pyridyne (pyridopyrimidinone),
- Pschorr ring closure and oxidative cyclisation to fused tri-cyclic heterocyclic systems,
- cyanomethylation and cyclization (imidazopyridine-1-oxide),
- [2+4] cycloaddition of pyridyl isocyanate and diazonium ions (azolotetrazinone),
- cyclization of isocyanate and aminopyrazolo carboxylate (pyrazolopyrimidinedione),
- new cross coupling reactions of nitropyridines,
- chiral pyridine products formed by [2+2+2] cycloaddition reactions,
- chiral hydroalkoxylation,
- Non Linear Optical (NLO) properties of isocyanurates,
- biological activity of potential products by bioassay screening.
A collaboration with research groups at the Universities of Hamburg and Tromsø will be establ ished.

Synthetic applications of nitropyridine derivatives.

Hydrogen production from natural gas with CO2 capture is of strategic importance in Norway. The project deals with a new technology using sorption enhanced reactions enabling to produce hydrogen form natural gas in one-step with CO2 capture. The multifunc tional reactor combines pre-reforming, metahne reforming, high temperature WGS, low temperature WGS and CO2 sorption process together in one-step. It is expected to significantly reduce investment costs and running cost, and thereby to achieve a cheep pro duction of hydrogen. The project aims at developing new active and stable catalysts suitable for sorption enhanced reactions, demonstrating relatively pure hydrogen production (>90%) with very low CO and CO2 using sorption enhanced reforming of natural ga s and sorption enhanced water gas shift reactions. The catalyst, integration between catalyst and sorbents, reaction conditions, sorbents regeneration and materials stability will be optimized to get maximum yield of hydrogen. Another objective is to gain  a better understanding of the reactions involved hydrogen production. Educating one Ph.D candidate and enhancement of national and international cooperation are expected results of the project.

Integrated process for hydrogen production with CO2 capture using sorption enhanced reactions

Synthesis gas can be produced by catalytic partial oxidation using gas phase oxygen. However, this process is facing some major engineering problems such as the presence of large temperature gradients and the risk of explosion caused by premixed methane a nd oxygen. An alternative approach is to carry out the partial oxidation by using lattice oxygen in a solid material, i.e. with no gas phase oxygen present. The present proposal deals with the studies of a reactor system where air and methane are periodic ally brought into contact with a catalyst consisting of convenient oxides such as perovskites or ceria based oxides. The redox process will be studied in a TEOM-MS reactor. The development of a microkinetic model based on the elementary steps of the surfa ce reactions is also an important part of the work.

Partial Oxidation of Methane. Studies on mechanism and kinetics.

The Tilset research group has recently developed the first members of a new class of chelating ligands, iminocarbenes, that form well-defined homogeneous Pd complexes with hemilabile, 5- and 6-membered, chelate structures. The use of these Pd complexes in  the catalytic transformation of organic molecules will be explored. In particular, reactions that involve C-C bond forming reactions will be explored, i.e. the so-called Heck, Stille, Suzuki, and Sonogashira couplings, as well as CO/ethene copolymerizati on. The results of the catalytic testing will be supplemented by mechanistic investigations. The combined insight gained will hopefully enable the design of even better catalysts.

Catalysis with Pd Complexes that have Chelating N-Heterocyclic Carbene Ligands

Tuberculosis (TB) is the major cause of death from a single infectious agent among adults in developing countries. Human immunodeficiency virus (HIV) infections have further increased TB morbidity and mortality. It has been estimated that ca. 30 million p eople will die from tuberculosiswithin the next 10 years. There is an urgent need for new antimycobacterials. Agents that reduce the duration and complexity of the current therapy would have a major inpact on overall cure rate. Lack of compliance with the  current therapy leads to drug resistance. For treatment of mycobacterial infections, organism-specific agents, preferably with a novel mechanism of action in order to avoid resistance as long as possible, are recommended. We have identified purine deriva tives as potent inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Generally low toxicity towards mammalian cells are observed and compounds active against a variety of single-drug resistant strains of Mtb have been found. Our findings points toward  a novel mechanism of action. We will synthesise antimycobacterial compounds with optimized structures with respect to antibacterial activity, toxicity and bioavailablility. Non-purine analogs of the knowm antimycobacterial purines will be improtant synth etic targets. Antibacterial effects and toxicity will be determined continously and direct further structure optimization. In addition to development of potential drug candidates and increased knowledge on SAR, it is expected that this project will result  in several novel selective syntheses of heterocyclic compounds. Transcriptional response-based signatures for the assignment of putative mode of action for the potential TB drugs will be used in order determine mechanism of action. Once the molecular tar get of the compounds is identified, a more rational approach to the structural optimalization may be possible, including docking studies etc.The most promising compounds from in vitro assays will be examined in vivo

VM-Vareproduksjon og materialforedling

Shaped castings of light metal (Stykkstøping av lettmetall)

Awarded: NOK 23.1 mill.

Funding scheme:

VM-Vareproduksjon og materialforedling

Funding Sources

Thematic Areas and Topics