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Limb wounds in horses are common, however healing is exceedingly slow and fraught with complications. Contrary to body wounds, limb wounds demonstrate only a small amount of wound contraction. The specialist procedure of applying split-thickness skin grafts to limb wounds stimulates wound contraction by unknown mechanisms. The objective of this project is to identify those mechanisms to develop a treatment strategy for equine limb wounds for use in general  practice. Limb wounds are severely impacting animal welfare due to an extended healing/treatment duration, and the risk of euthanasia due to a poor functional outcome. By stimulating wound contraction, healing time will be reduced, and the functional outcome improved, directly benefitting the welfare of wounded horse and reducing treatment cost for the owner. Aim: To identify dermal components stimulating wound contraction, and to develop this knowledge into future state-of-the-art treatment of equine limb wounds for use in general practice. Hypotheses: i) Application of dermal fractions to collagen gels seeded with equine fibroblasts will increase gel contraction in vitro; ii) Application of dermal fractions to experimental limb wounds in vivo, will increase wound contraction resulting in a faster healing time versus wounds treated by conventional methods. Methods: i) The contractile effect of different dermal components will be assessed in a collagen gel/ fibroblast model; ii) Identified dermal components will be tested in a standardized experimental limb wound model in vivo (n=5). Ultimately, results from this project are expected to improve wound treatment in horses, directly impacting animal welfare by reducing healing time and improving the functional outcome of wounded horses. This will also directly benefit horse owners and caretakers and making veterinarians able to offer better treatment solutions.

HESTEFORSK - Raskere og bedre sårheling hos hest med autologe hudkomponenter

Prosjektet «Wheelchair Activity Monitoring» (WHAM) sikter både på å øke fysisk aktivitet blant rullestolbrukere, og på å bidra til bredere mål om mangfold og inkludering av personer med nedsatt mobilitet, ved å fremme større tilgjengelighet og deltakelse gjennom innovativ teknologi og forskning.

Rullestolbrukere er tre til fem ganger mindre aktive enn den generelle befolkningen, noe som øker risikoen for å utvikle forebyggbare sykdommer. Selv om det finnes retningslinjer for fysisk aktivitet som er tilpasset rullestolbrukere, trenger vi fortsatt effektive måter å implementere disse på samt nøyaktig teknologi for å spore mulige endringer i fysisk aktivitet. WHAM har som mål å bidra til økt fysisk aktivitet blant rullestolbrukere ved å lage digitale verktøy for å monitorere og gi tilbakemelding på rullestolbrukerens aktivitet. WHAM består av tre faser: to år ved University of British Columbia (UBC), som inkluderer et samarbeid med eksperter innen atferdsendrings-intervensjoner for rullestolbrukere; ett år ved Norges teknisk-naturvitenskapelige universitet (NTNU) og et halvt år ved Maastricht Instruments - de to siste fasene er viet til å utvikle de digitale teknologiene. 

WHAMs mål er:
1)	Å teste effekten av et treningsprogram på fysisk aktivitetsnivå og fitness blant rullestolbrukere,
2)	Å utvikle nøyaktige algoritmer for monitorering av fysisk aktivitet blant rullestolbrukere,
3)	Å lage et system som både monitorerer og gir tilbakemelding på fysisk aktivitet blant rullestolbrukere.

Wheelchair users (WCU) are three to five times more inactive than the general population, leading to a high risk of developing preventable secondary conditions. Although physical activity (PA) guidelines have been specifically developed for WCU, we lack systematic approaches to implement them in practice, as well as valid algorithms to monitor PA change in WCU through sensor-based solutions. Accordingly, the overall scientific aim of the WHeelchair Activity Monitoring project (WHAM) is to advance PA research and practice in WCU by developing valid digital markers for monitoring of and providing feedback on PA, paving the way for implementation and intervention. I will accomplish this through combining the complementary research fields of 1) behavioral intervention studies focusing on increasing PA in WCU (core competence University of British Columbia, UBC; outgoing phase) and 2) sensor-based PA monitoring (core competence Norwegian University of Science and Technology, NTNU; returning phase – consolidated by non-academic placement at Maastricht Instruments, which develop research prototypes including PA monitors). WHAM’s scientific aim is achieved through three objectives: 1) Measure the effect of a pragmatic exercise intervention trial on self-reported physical activity levels and cardio-respiratory fitness, 2) Develop valid algorithms for tracking PA markers in WCU, and 3) Co-create
a framework that outlines how PA can be conjointly monitored and provided feedback on in WCU. This fellowship will enable me to become established as an internationally recognized researcher in the field of “physical activity and disability”, while bringing together ongoing national disjointed research activities in this field. Altogether, my overall ambition is to contribute to reducing inequalities in daily-life participation among WCU compared to the rest of the population.

Topfinancing - WHeelchair Activity Monitoring project (WHAM)

Effektene av fysisk og seksuell vold på ofre og deres familier kan være ødeleggende og vedvarende, med potensielt langvarige konsekvenser for fysisk og mental helse, utdanning, sysselsetting og bruk av velferdstjenester. Mens strafferettssystemet anses som en viktig del av offerets gjenopprettingsprosess, er det begrenset empirisk forskning på hvorvidt strafferettslige prosesser hjelper og/eller hindrer bedring langs disse ulike dimensjonene. I dette prosjektet vil vi adressere dette kunnskapshullet ved å bruke en kombinasjon av kvantitative og kvalitative forskningsmetoder. I de kvantitative analysene vil vi bruke administrative registerdata som dekker hele befolkningen sammen med kvasi-eksperimentelle metoder for å kunne trekke kausale slutninger. Vi vil også benytte maskinlæringsteknikker for prediksjon. De kvalitative analysene vil supplere de kvantitative analysene ved å gi kontekst til et komplekst felt av saker og ofre og ved å identifisere potensielle mekanismer mellom strafferettslige prosesser og utfall for ofrene. Samlet vil disse metodene gi en mer robust, representativ og nyansert forståelse av hvordan kontakt med strafferettssystemet påvirker offeret på tvers av flere viktige livsområder både på kort og lang sikt. Prosjektet ledes av Folkehelseinstituttet (FHI) med Frischsenteret og Universitetet i Oslo som partnere. Prosjektet har et rådgivende utvalg med medlemmer fra Nasjonalt kunnskapssenter om vold og traumatisk stress (NKVTS), ETH Zurich, Universitetet i Oslo, Frischsenteret, Universitetet i Bergen, og OsloMet. Det er også tilknyttet en brukergruppe bestående av personer og organisasjoner som er i kontakt med ofre for vold og overgrep.

Victims of sexual and physical violence is one of the most vulnerable groups in our society. The criminal justice system (CJS) serves a critical role in providing assistance to victims of these crimes, enabling them to seek justice, protection, compensation, and closure. Yet, knowledge about whether the CJS helps or harms these victims is extremely limited. This project aims to remedy this by providing a comprehensive understanding of the role of the CJS in supporting and providing restoration for victims of physical and sexual violence in Norway. We will utilize a combination of quantitative and qualitative research methods across disciplines to study outcomes across multiple important life domains, both in the short and long run. For the quantitative analyses we will use exceptionally rich longitudinal administrative register data with full population coverage combined with state-of-the-art quasi-experimental methods for credible causal inference and predictive machine learning techniques. The qualitative analysis will be based on narrative interviews with victims, providing context and insights into how interactions with the CJS shape life stories. The results will yield a robust and nuanced understanding of how the different stages of the CJS impacts victims. This is particularly urgent given how the current emphasis on legal responses to assaults has caused a sense of obligation and civic duty for especially women to report incidents, while the chances of legal closure remain small. In addition to advancing the methods for quasi-experimental designs and machine learning within quantitative criminology, this project will provide valuable insights for policymakers, stakeholders, and practitioners working in the field of victim support and rehabilitation and may inform current legal reform efforts aimed at addressing these issues.

Helpful or harmful: The effects of criminal justice system contact on victims of sexual and physical violence

The goal of the Bilingual Experiences, Cognitive Ageing and underlying Mechanisms (BECAME) project is to examine the functional neuroplastic mechanisms underlying mitigatory effects of bilingual experience on age-related cognitive decline. While evidence is available for structural brain changes supporting bilingualism-induced effects on cognitive aging (CA), functional mechanisms underlying such effects are not yet well understood. BECAME aims to fill this gap by investigating the trajectory of bilingualism-induced functional neuroplasticity across the adult lifespan (ages 18-85), crucially adopting an individual differences approach related to measurable degree of bilingual engagement. Importantly, although such benefits are thought to be rooted early in the lifespan, evidence for the timeframe and conditions of their early emergence is scarce. The choice of including the whole adult lifespan allows us to investigate these mechanisms and their emergence more directly from a lifespan perspective. I combine behavioral testing with brain recordings via electroencephalography (EEG). EEG is widely used in cognitive neuroscience to assess brain activity and the degree of communication between brain regions (functional connectivity) in response to stimuli and at rest. Combining behavioral and EEG modalities will allow me to test bilingualism’s effect on functional connectivity, as well as its consequences for functional efficiency, the minimum required neural activation to successfully perform a task. This will enable a detailed, evidence-based account of the protective effects observed in older-aged bilinguals, and how they are built from earlier life stages. By illuminating the relationship between multilingualism and resulting neurocognitive adaptations, BECAME will enable to capitalize on it as a health initiative, with manifold societal implications and the potential to be translated into actionable policies exploiting multilingualism to ameliorate effects of CA.

Bilingual Experiences, Cognitive Ageing and underlying Mechanisms

From the SEA to the SOLution. An integrative assessment of marine pollution in a changing Arctic

Marine chemical pollution poses known threats to human health and to biodiversity, ecosystem and societal services. The Arctic is a major sink of global mercury (Hg) pollution. Arctic sediments, sea and glacial ice constitute vast Hg reservoirs. Recent studies raise concerns about their increasing role as local Hg sources. In a rapidly warming Arctic, the consequences of potentially increased environmental Hg on marine biota remain unknown. The objective of SEASOL is to identify the pathway(s) of Hg bioaccumulation in marine food webs of the High Arctic Kongsfjorden (Svalbard). This changing glacial fjord is recognised as a ‘natural laboratory’ of climate change in the Arctic. The fellow’s earlier research has shown the sole measurement of Hg levels as insufficient to connect biotic Hg dynamics to environmental change, whereas the analysis of Hg stable isotopes proved to be a promising tool for source discrimination and biotic transfer. SEASOL will build on the novel application of stable isotope analysis to identify the sources of Hg within the fjord system and the pathways to Hg accumulation within sentinel marine species. On the short-term, the study will provide fundamental knowledge to help understand how emerging sources of Hg from rapid environmental change will impact Arctic marine predators. On the long-term, SEASOL will contribute to the development of early-warning, adaptive management strategies, including modelling, for mitigating the cumulative impact of pollutants and climate change on Arctic marine species. This multidisciplinary approach and the central position of the host institution (Norwegian Polar Institute) in the field of Polar Research will equip the Fellow with a broad set of new skills and lay the foundation for building her specific niche as a future leader in marine pollution science.

Reality-Connected Machine Simulation of Heavy Machinery

The RealSim project proposal aims to connect machine simulation to reality in the framework of heavy machinery, which is an interdisciplinary application. The results of this project are expected to optimize machine performance, accurately and reliably predict machine failure, and reduce overall development and operation costs, thus, serving the Europe’s priority of green transformation and the United Nation’s sustainable development goal 9. The RealSim project will close the gaps of: (1) Onboard estimations of force and pressure components of heavy machinery; (2) Estimating deformability, cylinder friction, leakage, and valve dynamics of heavy machinery using independent nonlinear Kalman filters; (3) Employing dependent nonlinear Kalman filters in state estimators of heavy machinery; (4) Tuning algorithms for the covariance matrix of plant noise in the state estimation of heavy machinery. 

I will consolidate and leverage my research career and position as a leading researcher in the field through integration in Assoc. Prof. Mohammad Poursina’s group at the Department of Engineering Sciences of the University of Agder (UiA), Norway. Here, I will acquire hands-on experience of working with actual mechatronic systems and develop efficient control algorithms. I will improve my knowledge of fluid power designing, control theory, instrumentation, and develop efficient coding skills. I will also develop entrepreneurial skills. The skills, knowledge, and international network that I will develop during this fellowship will put me in an excellent position to achieve my long-term goal of becoming a professor with my own independent research group at an esteemed university in EU. This fellowship will help me to prepare a strong ERC Starting Grant application in the future. It will also cater my additional goal of setting-up a research-related start-up in the future.

Information theory is a discipline at the intersection of statistics, engineering and computer science. As the study of information quantities, such as compression or communication capacities, information content or measures of statistical dependency, it is one of the theoretical underpinnings of data science.

Computational problems in information theory are highly non-linear. The goal of this project is to transfer state-of-the-art methods of computational non-linear algebra to information theory, to study the inherent algebraic complexity of information-theoretical problems and to provide tools for solving them in practice. The algebraic point of view has proven to be fruitful in seemingly unrelated areas, as witnessed by a surge of recent work in algebraic statistics, in particular on likelihood geometry. However, maximizing the likelihood function is the same as minimizing relative entropy — a specific information quantity. Hence, this project also aims at generalizing the techniques developed in likelihood geometry.

One focus is on the practical computation of information quantities using numerical and differential algebraic geometry. Such quantities are defined via non-linear optimization problems and we aim to pinpoint the algebraic complexity of these problems in instances of general interest, such as common information measures. The final objective is finding fundamental laws and limits of data science imposed by non-linear inequalities constraining the entropic region. These inequalities provide, by duality, universal bounds for many of the optimization problems studied in information theory.

Algebraic Theory of Information Quantities

Enabling the next generation in search of blood cancer cures

The CarrerasPathfinder program is new a world-wide unique doctoral program that covers the entire spectrum of research and innovation in blood cancers from understanding disease biology to the implementation of novel processes in the clinical practice. The program will fund 14 excellent Doctoral Candidates (DCs) for a period of 48 months. DCs will perform collaborative PhD projects involving associated partners from different sectors, countries, and disciplines through secondments. DCs will improve their research capacity and transferable skills through high-quality supervision arrangements and a tailored training program.

The program has been designed and will be hosted by the Josep Carreras Leukaemia Research Institute (IJC) which is the first European non-profit institute exclusively devoted to blood cancers. By answering the European needs for human resources, it is fully aligned with the 13 recommendations of the EU Cancer Board’s Draft Mission  and the Europe’s Beating Cancer Plan (2021). The CarrerasPathfinder program has a strong triple-I dimension of internationality, inter-sectorality and interdisciplinarity in training, networking, co-supervision and research. Its specific objectives are:
•	To develop an excellent doctoral program in blood cancer research conceived as a pilot for a permanent international doctoral program
•	To equip DCs with a unique skill set boosting effectiveness and innovation capacity. 
•	To promote DCs’ career development and increase their employability in different sectors.
•	To establish the IJC as a European reference for research and training in blood cancers.
•	To provide Europe with a new generation of researchers able to address unmet needs and societal challenges of blood cancers.
•	To contribute to structuring the European research area by collaborating and synergizing with other European key opinion leaders.



Tenk på universet som en enorm ballong som alltid utvider seg. Jo lenger unna et punkt er på ballongen, jo raskere beveger det seg bort fra deg. Dette ligner på hvordan universet utvider seg, jo lenger unna en galakse er, jo raskere beveger den seg bort fra oss på jorden.

I mange år trodde forskerne at universets ekspansjon ble bremset. Begrunnelsen deres var at gravitasjonskraften fra all materie i universet virket mot denne utvidelsen. Imidlertid gjorde kosmologer i 1998 en overraskende oppdagelse gjennom studiet av fjerne supernovaer: utvidelsen av universet akselererer faktisk!

Dette betyr at avstanden mellom galaksene blir større og større i stadig økende hastighet. Det er som om ballongen blåses opp raskere og raskere.

Forskere vet ikke nøyaktig hva som får universet til å akselerere. De kaller den ukjente kraften som får dette til å skje "mørk energi". Mørk energi er overalt i universet, men den mørke energien vekselvirker ikke med materie i de formene som vi kan observere direkte.

NEVO-prosjektet er et nytt forsøk på å forstå egenskapene til mørk energi. NEVO vil bruke kraftige datamaskiner for å simulere universet og studere effekten av kandidater til den mørke energien på en måte som aldri har vært gjort før. Ved å studere disse simuleringene og utnytte høypresisjons-observasjonene fra Euclid-teleskopet som nylig er skutt opp i rommet, vil kosmologene være i stand til å bedre betydelig vår forståelse av den mørke energiens gåtefulle natur.

The Universe has entered an accelerating expansion phase in the last few billion years of its evolution, a phenomenon that is caused by the mysterious entity known as dark energy. Through the NEVO proposal, I aim to provide key insights about the properties of dark energy, which includes its time evolution and spatial distribution in the Universe. This objective will be achieved by utilizing cutting-edge cosmological N-body simulations and novel techniques to study cosmic EVOlution accurately.

A comprehensive understanding of the nature of dark energy requires a thorough investigation of viable candidates and their impact on different stages of the Universe. However, the consistent and accurate modeling of dark energy candidates has been largely neglected so far. To address this gap, I propose the development of a novel, integrated framework that utilizes state-of-the-art relativistic N-body simulations along with the hi_class code, to accurately model dark energy candidates in both linear and non-linear scales.

NEVO: illuminating the dark cosmos

Global natur- og miljøforvaltning er en av vår tids mest sentralt og vanskellige mål. Mange av utfordringene skyldes motsetningene mellom vår fragmenterte politiske verden og økosystemer som ikke forholder seg til landegrenser eller politiske skillelinjer.
Ulike biologiske samfunn (biomer) som ligger i én stat, kan ikke løsrives fra et større økosystem. Derfor er flere «lokale» naturområder blitt del av den globale miljøforvaltningen.
Prosjektet RESOLVING skal se på politiske løsninger for en naturforvaltning som både er:
(i) lokal: som del av en stats territorium og hjem til ulike befolkningsgrupper
(ii) global: som kritiske deler av planetens økosystem
Hva betyr denne forvaltningen på flere nivåer for staters suverenitet?
Vi vet allerede mye om utfordringene nasjonalt oppdelt myndighet utgjør for effektiv forvaltning av jordens økosystemer. Vi vet derimot langt mindre om hvordan forsøkene på å styre jordens komplekse og grenseløse økosystemer faktisk kan endre selve systemet som forsinker den globale forvaltningen: statlig suverenitet.
RESOLVING vil prøve å forstå denne dynamikken ved å undersøke gruppene som faktisk utøver internasjonal naturforvaltning på vegne av eller parallelt med statene. Prosjektet vil her se nærmere på styringen av to områder som er viktige for hele verden: Amazonas-regnskogen og Guineabukta.
RESOLVING undersøker hvordan tiltak for å ta vare på disse områdene – laget på både internasjonalt, nasjonalt og lokalt nivå – fungerer sammen. Hvilke aktører får mer makt? Hvem blir inkludert i beslutningsprosessene og hvem blir utelatt?

The RESOLVING project asks: How does global governance of nature transform the exercise of sovereign power? Scientific evidence of the environment as a complex system of planetary dimensions has elevated several natural resources as objects of global governance. Primary forests and maritime biomes particularly capture global attention because of their systemic relevance for our planetary ecosystem. Still, international politics operates within a framework locating authority over nature indivisibly into territorially discrete and independent states. This project investigates the implications for sovereignty stemming from the construction of nature as a global governance object. We build on existing conceptualizations of sovereignty as a combination of de jure sovereign authority and bundles of de facto sovereign competence. In the case of nature, while permanent sovereignty over natural resources is an immutable property of state authority, a wider range of actors can be involved in defining the ways in which these resources are governed or even in governing them. RESOLVING will focus on two parcels of local nature especially entangled in global governance: the Amazon rainforest and the Gulf of Guinea. The project will investigate how networks of actors work across levels of governance to produce sovereign competence and exert sovereign power over nature in these regions. Sovereign power is the capacity to achieve de facto sovereign competence, here identified as the capacity to define and implement the rules of human–nature interaction. We look at multilevel governance from three angles: the global, the state, and the local. The comparative analysis of those networks across levels, regions, and regimes complexes will allow for identifying the mechanisms driving the rebundling of sovereign power with or away from the state, and a better understanding of the consequences of that process.

Rebundling sovereignty over local nature in global governance

Midlene fra HAVBRUK2-Stort program for havbruksforskning fordelt på år

Midlene fra HAVBRUK2-Stort program for havbruksforskning fordelt på fylker

Midlene fra HAVBRUK2-Stort program for havbruksforskning fordelt på fagområde

Senior Scientist

Production of fish in land-based aquaculture contributes significantly to the production of animal protein in the human food-supply chain in the Nordic countries. Recirculation aquaculture systems (RAS) provide an environmentally sustainable solution that is becoming more and more relevant for current production systems.
However, considerable challenges with these production systems means narrow production margins and uncertainties regarding fish health and production performance.

An extensive amount of information on water quality, feed use and health parameters are gathered through monitoring of the fish and their environment via sensors. In most cases, these data are stored in separate datasystems, not utilizing the huge potential for more precise monitoring and reporting of the realtime health, welfare and growth of the fish.
We aim to integrate such data from many farms and production cycles and through the usage of Artificial Intelligence (AI), enabling the farmers to move from experience-based to knowledge-based decision making. This will enable a more sustainable production with regards to production margins, environmental impact and fish health and -welfare.

Specific objectives of the project are: 
* Integrating several sources of bigdata including data on water quality, feed usage, health and production
* Developing a deep learning-based prototype system for audiovisual monitoring of fish behaviour in RAS farms
* Development of a dynamic growth model that include multiple data sources
* Implementation of precision fish farming system for optimal production
* Development of a health monitoring system.

The best indicator of health and well-being is the fish's own behavior. In the project, deep learning tools are used on video sequences of fish, i.e. teach computer systems how the fish react in different situations. In two RAS facilities, the fish's surface activity has been filmed, and a selection of video sequences has subsequently been annotated, i.e. people have marked what the fish's head is in the videos. These annotations have been used to train the system to recognize the fish, and be able to follow its movements in the tank. In this way, we have created an algorithm for normal behaviour. In the last part of the project, feeding experiments are carried out, so that the system can be trained to recognize feeding behaviour.

In order to find out how the fish are affected by the production system, extensive welfare and disease investigations have been carried out on the fish in the two facilities. Similar investigations have been carried out at two other RAS facilities. During 2021-2023, we have followed 18 fish groups at the four facilities. Each fish group has been examined at least once, and in total there have been 41 examinations of a total of 2,828 fish. For the survey, we have used the system for scoring external welfare indicators from the Fishwell handbook. We found, that 98% of all fish have fin damage, and that these damages change over time, both in severity and which fins are most damaged. The results from the surveys have not been finalized yet, but will be published at the beginning of 2024.

Production data, and data on feed consumption and environmental monitoring are also collected from all four RAS-farms. With these data, we will examine whether any health and welfare challenges are reflected in the collected data.

In addition, production data from 15 RAS farms has been collected, and these are now being used to develop a model that should be able to detect deviations from normal or expected mortality, based on daily data. This data collection has also provided an insight into what types of data actually exist in RAS production in the Nordic countries. And also which types of measurements are or will be automated. In this way, we will get an overview of the status quo for the use of "big data" in RAS production, and be able to make suggestions for improvements.

Production of fish in land-based aquaculture contributes significantly to the production of animal protein in the human food-supply chain in the Nordic countries.  Recirculation aquaculture systems (RAS) provide an environmentally sustainable solution that is becoming more and more relevant for current production systems. However, considerable challenges with these production systems means narrow production margins and uncertainties regarding fish health and production performance. 

An extensive amount of information on water quality, feed use and health parameters are gathered through monitoring of the fish and their environment via sensors.  In most cases, these data are stored in separate datasystems, not utilizing the huge potential for more precise monitoring and reporting of the realtime health, welfare and growth of the fish.

We aim to integrate such data from many farms and production cycles and through the usage of Artificial Intelligence (AI), enabling the farmers to move from experience-based to knowledge-based decision making. This will enable a more sustainable production with regards to production margins, environmental impact and fish health and -welfare.

The best indicator of health and performance is the behaviour of the fish themselves. One major challenge in RAS is waste of feed. We will use AI and statistical models to develop a closed loop control of feeding to reduce feed waste and optimize growth, moving from a manual analysis and response to a knowledge-based automatic one. This will be done by the application of deep learning tools on video sequences of fish, teaching computer systems how the fish react when they are hungry and when they have been feed. 

In addition, statistical models will be used on the integrated datasources and video sequences to develop a system for early detection and warning of upcoming disease events, thus giving the farmer time to react in the narrow time-window between an adverse health event and death.

NordForsk - Intelligent farming and health control in landbased recirculating aquaculture systems

Hjertesvikt er et økende problem i samfunnet og vi har behov for bedre hjertesviktbehandling. Dette krever bedre forståelse av mekanismen for hjertets funksjon både i normale og sviktende hjerter. I hjertesvikt klarer ikke hjertet lenger å pumpe nok blod til resten av kroppen. Det er to hovedgrupper for hjertesvikt, i den ene gruppen trekker ikke hjertet seg godt nok sammen, mens i den andre gruppen fyller ikke hjertet seg godt nok med blod mellom slagene. Begge formene for hjertesvikt resulterer i utilstrekkelig pumping av blod fra hjertet til resten av kroppen. Hjertehormonene natriuretiske peptider har i de senere årene mottatt mye oppmerksomhet som potensiell hjertesviktbehandling. Men de direkte effektene på hjertet er fortsatt ikke klarlagt. Legemidler som øker natriuretiske peptider i kroppen har nylig blitt godkjent for bruk i hjertesviktbehandling. Videre har legemidler som etterligner effekten av natriuretiske peptider blitt foreslått som hjertesviktbehandling i mange år. Det er fortsatt behov for mer kunnskap om både gunstige og ugunstige effekter av natriuretiske peptider i hjertet. Vi fant nylig at natriuretiske peptider er involvert i hjertets evne til å trekke seg sammen. Videre har vi resultater som viser at ulike proteiner kan regulere effektene av natriuretiske peptider i hjertet.  I dette prosjektet, ser vi på rollen til en av disse proteinfamiliene som kan regulere ulike funksjonelle effekter av natriuretiske peptider i normale og sviktende hjerter. Foreløpige resultater viser at denne familien proteiner er uttrykt i hjertet, påvirker natriuretisk peptid signallering og kan potensielt påvirke effekten av natriuretiske peptider på hjertets sammentrekning. Prosjektet vil øke kunnskap om natriuretiske peptider og proteiner som regulerer disse i hjertet og forhåpentligvis forbedre fremtidig hjertesviktbehandling.

Heart failure (HF) is still an increasing problem in the society and we are in need for better HF treatment. This requires better understanding of the mechanisms of myocardial function in normal and failing hearts. In heart failure the heart is no longer able to pump sufficient blood to the body. There are two main subgroups of heart failure, diastolic/HFpEF (HF with preserved ejection fraction) and systolic/HFrEF (HF with reserved ejection fraction) heart failure. In HFrEF the heart doesn't contract sufficiently, whereas in HFpEF the heart doesn’t fill with blood sufficiently. Both HFrEF and HFpEF results in insufficient pumping of blood to the body by the heart. The cardiac hormones natriuretic peptides have the recent years received much attention as potential heart failure therapy. However, the direct effect at the heart is still elusive. Drugs increasing natriuretic peptides have recently been approved for the use in heart failure. Further, drugs that mimic the effect of natriuretic peptides have for several years been suggested in treatment of heart failure.  There is still need for more knowledge about beneficial and detrimental effects of natriuretic peptides in the heart. We recently found that natriuretic peptides is involved in the hearts ability to contract. Further, we have results showing that different proteins can regulate the effects of natriuretic peptides in the heart. In the suggested project, we will study the role of these proteins in the regulation of different functional responses of natriuretic peptides in normal and failing hearts. This project will increase our knowledge about interacting proteins of natriuretic peptide receptors, natriuretic peptides and of the intracellular mechanisms governing heart function and hopefully contribute to new possible targets and improved treatment of heart failure in the future.

CyTOheart: Cytohesins in the heart - regulation of natriuretic peptide signaling

Behandlingsresistent hypertensjon (RHT) er et økende problem og kan være årsak til for tidlig sykelighet og død. RHT er definert som høyt blodtrykk til tross for at pasienten bruker tre ulike legemiddelgrupper mot høyt blodtrykk. Prevalensen fortsetter å øke. Utvikling av et nytt legemiddel som kan kontrollere det økte blodtrykket i disse pasientene haster og har høy sosial og klinisk betydning for mange millioner mennesker på verdensbasis. Natriuretiske peptider spiller en viktig rolle i reguleringen av blodtrykket og det er vist at pasienter med RHT har forstyrrelser i natriuretisk peptid-systemet. I dette prosjektet utvikler vi småmolekylære stoffer hvor natriuretisk peptid reseptor-A  (NPR-A) er målet for behandling av pasienter med resistent hypertensjon. Vi har tidligere identifisert ligander med aktivitet gjennom "high-troughput screening" og "in-silico design" og har jobbet med å utvikle disse stoffene for å bedre farmakologiske egenskaper. Vi har opparbeidet oss et stort bibliotek av stoffer og økt vår kunnskap om struktur-aktivitetsforholdet til stoffene og har nå bestemt oss for en kandidat vi ønsker å gå videre med. Dette stoffet viste lav toksisitet i prekliniske celleforsøk og høy selektivitet for NPR-A sammenlignet med et farmakologisk panel av reseptorer, enzymer, transportere og ionekanaler. Vi er nå klare til å starte en «proof-of-concept» studie i en dyremodell med hypertensjon. Vårt langsiktige mål er å kunne tilby god behandling til pasienter med ukontrollert høyt blodtrykk.

Resistant hypertension (RHT) is a frequent disease and causes premature morbidity and death. RHT is defined as high blood pressure that remains above goal despite the use of three antihypertensive drugs of different classes. The prevalence of RHT continues to rise. Thus, the development of novel drugs that can control the elevated blood pressure in these patients is urgent and of high social and clinical impact for several millions of people worldwide. Natriuretic peptides play an important role in the regulation of blood pressure and it is shown that patients with RHT have an impaired natriuretic peptide system. In this project we are developing small molecular compounds to target the natriuretic peptide receptor-A (NPR-A) for the treatment of patients with resistant hypertension. We have recently performed a high-throughput screening and identified three compounds showing activity. We further want to develop these compounds to improve the pharmacological properties with the goal to go through a proof-of-concept study in an animal model of hypertension at the end of the project period. Thus, in this project we will further synthesize novel compounds and the best active compounds will go through preclinical cytotoxicity and pharmacokinetic testing to enable a proof-of-concept study. Our long-term goal is to offer a good treatment for patients with uncontrolled high blood pressure.

Optimalisering: Novel therapy for treatment-resistant hypertension

Forekomsten av alvorlig hjertesykdom øker i befolkningen og det er stadig behov for bedre behandling. Hjertesvikt kan oppstå etter f.eks. hjerteinfarkt eller langvarig høyt blodtrykk og karakteriseres ved at hjertets pumpeevne er svekket. Pasientene har ulik grad av redusert ytelsesevne, pusteproblemer og væskeansamling i kroppen. Ettersom flere overlever akutt hjertesykdom øker også forekomsten av pasienter med hjertesvikt. Økt forståelse for hva som skjer ved utvikling av hjertesvikt har ført til bedre behandling av pasientene. Det er nå forståelse for at kroppen kompenserer for hjertets svekkede pumpeevne. Dette er mekanismer som på kort sikt kan være gunstige, men som på lang sikt kan forverre hjertesvikten. Dagens behandling er basert på dette. Til tross for at mye har skjedd de siste 30 årene i forståelsen for hjertesvikt, er det likevel behov for mer kunnskap om sykdomsutviklingen og om nye angrepspunkter i behandlingen. Det er vist at signalstoffer som til tross for at de påvirker de samme signalsystemene i hjertet, likevel kan gi ulike effekter. I prosjektet har vi studert proteiner som vi mener kan bidra til at forskjellige stimuli gir forskjellige effekter på hjertets kontraksjonsevne selv om de benytter de samme signalsystemene inne i hjertemuskelcellene.  Vi har nå funnet proteiner som ser ut til å regulere det samme signalstoffet ulikt avhengig av hvilke stimuli som gis. Vi mener derfor disse proteinene kan ha betydning for forskjellene vi ser på ulike stimulis effekter på hjertets kontraksjonsevne. Vi vil fortsette arbeidet i nye prosjekter med å se på betydning av disse proteinene for kontraksjon og hva disse mekanismene betyr i utviklingen av hjertesvikt. Prosjektene vil på lang sikt kunne bidra til å utvikle nye og bedre legemidler til bruk ved hjertesvikt.

We are in need for better heart failure (HF) treatment. This requires better understanding of the mechanisms of myocardial function in normal and failing hearts. It is known that receptors increasing the same signalling molecule cause differential effects , i.e both beta-adrenoceptor (beta-AR) and prostaglandin receptor stimulation increases cAMP, but only beta-AR stimulation causes inotropic response. Recently, we found that C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP), both increa sing cGMP, affected cAMP-mediated inotropic response differently in failing hearts. CNP, activating the NPR-B receptor, increased both beta1-AR- and 5-HT4-R-induced inotropic response, whereas BNP, activating the NPR-A receptor, had no effect. Furthermore , CNP alone caused a negative inotropic response, whereas BNP did not. Phosphodiesterases (PDEs) are key regulators of cyclic nucleotide signalling involved in compartmentation of functional effects. However, regulation by PDEs is not the complete answer  to why some receptors cause contractile effects, whereas others do not. A plausible explanation for these differential effects could be different location of receptors and different intracellular binding partners. 
With a proteomic approach we will identi fy proteins that bind to the NPR-A and NPR-B receptors. This will generate a lot of information in a field largely unexplored (cGMP system) and reveal information about which proteins may be important in compartmentation of not only the NPR-A and NPR-B re ceptors, but also of G-protein-coupled receptor signalling as we know that NPR-B is linked to both the beta1-AR and 5-HT4-R in the contractile machinery, whereas NPR-A is not. The role of interesting proteins will be explored  (by using shRNA techniques)  with respect to contractile effects and compartmented cAMP/cGMP levels in normal and failing rat hearts. This project may generate information on proteins important to target in HF.

0 projects

FRIPRO-Fri prosjektstøtte

CyTOheart: Cytohesins in the heart - regulation of natriuretic peptide signaling

Awarded: NOK 8.0 mill.

Project Period: 2020-2024

Location: Oslo

BIOTEK2021-Bioteknologi for verdiskaping

Optimalisering: Novel therapy for treatment-resistant hypertension

Awarded: NOK 8.0 mill.

Project Period: 2018-2021

Location: Oslo

FRIMEDBIO-Fri prosj.st. med.,helse,biol

The role of binding proteins in compartmentation of cAMP and cGMP signalling in normal and failing hearts

Awarded: NOK 3.5 mill.

Project Period: 2013-2017

Location: Oslo