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Chemosensation is a critical signalling process for sea cucumbers which relies on the interaction between their chemosensory receptors and various ligands for foraging and reproduction. Although there is a vast amount of research on the chemistry of secreted specialized metabolites of sea cucumbers, and some behavioural data evidencing chemoreception of these metabolites, the chemosensory receptors of these organisms have not yet been identified and nothing is known about the physiology behind sea cucumber chemosensation. This setback is in large part because the scientific approach behind studying chemosensation requires a vast array of techniques and expertise in ethology, chemistry, molecular biology, and biophysics.  Firstly, a behaviour associated with a chemical cue must be quantifiable, secondly, the precise chemical cue eliciting the behaviour response must be identified and isolated, thirdly, the chemosensory receptor of this specific cue needs to be identified on a tissue, cellular, and molecular level, and finally, the activation of this specific receptor by a specific chemical cue must elicit a measurable response on a molecular, cellular, tissue, and organismal level. Through this project, I will elucidate the physiology of chemical communication between sea cucumber by considering these sequential steps in chemosensation. With my previous experience in sea cucumber ethology and chemistry, SensHolo will enrich my skill base in molecular biology and biophysics so that the mechanisms behind intraspecific chemical communication between sea cucumbers may be determined from both the emitter and receiver perspective; from signal to receptor.  This holistic approach will be ground-breaking in chemosensation and sea cucumber research. It will enable future research to address the evolution of chemosensation in marine invertebrates and the chemical ecology of sea cucumbers both in the context of optimizing aquaculture and in their ecological conservation.

Chemosensation in Holothruoids

Extending Techniques in Wall-Crossing and Enumerative Sheaf Theory

The goal of ExtWest (Applying and Extending Techniques in Wall-Crossing and Enumerative Sheaf Theory) is twofold: First, we plan to find and realize new applications of the recent technical developments in the field of enumerative sheaf theory, thereby proving new groundbreaking results. Second, we plan to develop new techniques inspired by the extisting results, and to thereby extend the range of accessible questions in this research area.

RMIT EU spearheads the Driving Climate Positive Futures (DREAM+PLAN), a truly interdisciplinary, international and intersectoral PhD program, uniting European and Australian research via 32 doctoral positions for double degree.  DREAM+PLAN brings together a community of visionary changemakers, leaders, who dream big and develop tangible pathways for solving local and global climate-related challenges, all united by a mission to create a positive impact, towards a more sustainable, fair, inclusive and thriving planet for future generations.  The need for  1. resilience (ability to withstand and recover from disruptions),  2. restoration (ability to repair or rehabilitate degraded ecosystems) and  3. regeneration (fostering the renewal, revitalization and replenishment of ecosystems, communities)  research is more acute than ever.   The overarching objectives of DREAM+PLAN research training program is to create and deliver, legacy-worthy, novel, cutting-edge, 3i-centric training through best-practice multi-faceted, multi-modal group and individual training options for DCs. Ultimately, breeding the next generation of high-performing ESRs equipped with a unique set of skills and capabilities to fully comprehend and address the multifaceted nature and scale of climate change, across sectors.  DREAM+PLAN’s training program is aligned to contribute to EU Missions, the European Green Deal and supporting RIS3 strategies and includes 3 annual doctoral schools, adopting a novel scaffolding approach.  DREAM+PLAN will fully embrace diversity and through its ecosystem approach, develop pathways for ESRs towards new mindsets, behaviours, technologies, policies supporting the transition to more sustainable, fairer, and productive futures. 

Driving Climate Positive Futures

Deciphering Evolutionary Innovations: Comparative genomics of the origin and loss of venom in marine snails

The VENORIGN project aims to understand the evolution of novelty in biology. A major goal of contemporary evolutionary biology is to decipher the molecular basis of major phenotypic innovations in organisms, such as winged flight in birds and echolocation in whales. However, most cases of evolutionary novelty involve complex interactions among multiple genes, each with only minor effects. To address this challenge, we turn to venomous marine snails, specifically the Conoidea group, which includes cone snails and related species. Venom in these snails is linked to a limited set of proteins called toxins, representing the primary genetic changes responsible for the shift from non-venomous to venomous animals. The long-standing interest in cone snail toxins provides a unique context for studying this transition. Yet, the origins of the conoidean venom system and the processes governing multiple venom losses remain poorly understood. This project tests the hypothesis that the origin and loss of conoidean venom resulted from rapid genomic and morphological changes and will investigate these genetic and morphological alterations driving venom's emergence and disappearance. Using cutting-edge methods spanning morphology, taxonomy, genomics, and transcriptomics, we will analyze venomous and non-venomous conoidean and related species. This comprehensive comparison will reveal the processes governing venom acquisition and loss, shedding light on the principles of evolutionary novelty. Our work extends beyond venomous snails, offering a novel model to understand the molecular foundations of significant evolutionary changes. These findings will contribute to our understanding of how novel traits emerge in various biological systems, including human pathogens and agricultural development.

Due to its multidrug resistance (MDR), Enterococcus faecium (Efm) poses a challenge to the healthcare system and renders most standard antibiotics useless.  Bacteriophage (phage) therapy has resurfaced as a treatment strategy for bacterial infections due to increasing antibiotic resistance. Its advantages include specificity, low side effects and production costs, especially when used in combination with standard-of-care antibiotics.  Phage therapy has been successful in compassionate use, but its wider implementation is hindered by a lack of knowledge on which antibiotics phages synergize and the mechanisms behind remain elusive.  Our project is unique in that it aims to enable the use of conventional antibiotics in MDR Efm through phages. We want to explore which antibiotic classes phages synergize with, which survival strategies Efm uses against phages, and how host factors influence the ability of the antibiotic-phage combination to kill Efm. First, we will investigate phages' interaction with different antibiotic classes against Efm. We will explore the dynamics of phage-antibiotic combinations and whether they are additive, synergistic, or antagonistic. Second, potential phage survival strategies of Efm will be investigated. Additionally, membrane vesicles will be investigated as a potential survival strategy against phages, and their ability to act as a decoy and protect the bacterium from phages will be studied. Third, we will investigate the impact of host factors on the phage-antibiotic killing of Efm, to see whether they can enhance or suppress the phage-antibiotic killing. This approach will provide a deeper understanding of the phages-antibiotic interaction against MDR Efm strains, as well as potential survival systems of Efm which may also shed light on possible mitigation strategies.  Overall, this approach has the potential to enable the use of standard-of-care drugs against MDR bacterial infections in general.

Phages against MDR Enterococcus faecium

HydroConnect focuses on the connectivities afforded by hidden, underground fresh water that surfaces along the coastlines of islands lacking accessible, perennial fresh water. It explores how Austronesian-speaking seafarers transformed such freshwater ‘seeps’ into wells throughout the South China Sea and Indo-Pacific, affording sea-routes around these well networks. Thus, HydroConnect breaks with the tendency in the social sciences and historiography to analytically privilege oceans or navigable rivers as vectors of global connections and history-making.  With the innovative concept of hydroconnectivities – human connections afforded by fresh water access – HydroConnect develops a novel theoretical framework linking the terrestrial and the aquatic through comparative historical ethnography of Austronesian speakers’ Indigenous knowledge, which has crossed oceans and flowed down generations, travelling between different groups of people. Deploying a cyclical tidalectic methodology transcending anthropology, archaeology and geology, it breaks new methodological and theoretical ground for conceptualising global history through hydrological connectivities across these chains of island worlds in different oceans.  First, it studies how this travelling Indigenous knowledge enabled hydroconnectivities that opened up sea routes and integrated fresh water, well infrastructure, and ecological and social exchanges across immense oceanic spaces in the past. Second, the project maps and theorizes how present-day descendants and successors of Austronesian-speaking seafarers benefit from vernacular hydrological knowledge of underground freshwater seeps. Thus, it advances analogical knowledge for tackling groundwater depletion to enable past-informed and future-oriented water policies for the sustainable management of the Earth’s aquifers. 

Global Hydroconnectivities beyond Oceans, Seas and Rivers

Health, European Muslims and Gender: Medical Authority and Assisted Reproductive Technologies in Sunni Islam

Infertility is estimated to affect an average of 14% people worldwide. It is an issue that affects equally both men and women, although it is often associated with a women’s social burden and the case of Islam is not an exception. While religion influences Muslims’ health beliefs, behaviours and decisions, health providers are not always aware of cultural and religious preferences and norms. Thus, Islamic norms on health treatments can result in Muslim’s exclusion from the health care system, especially affecting Muslim women. This can especially impact issues on infertility and reproduction, which holds exceptional moral and social significance across religions. Through an innovative focus, this project aims to advance scientific knowledge about how Sunni Muslims in a minority context in Europe navigate between the authority of medical science and the authority of religion, and to what extent this affect their access to health care.. The project will provide empirical data and develop a theoretical framework based on gender studies, sociology of religion and anthropology of health literatures. This will be achieved by applying intersectional perspective and qualitative methodologies, consisting of semi-structured interviews with Health Professionals and Muslims who have had fertility treatments. The research will be conducted in two European cities: Oslo and Barcelona. Both cities have experienced a rapid increase in religious diversity in last decades but are different in their organisation of religious communities and of health systems. The comparison between the two cities will provide insights into differences among Sunni Muslims around negotiating health, religious and gender issues. This project will contribute to new avenues of investigation concerning the life conditions of Sunni Muslims in Europe and will develop new knowledge on health inequality that may be adapted for future research on other religious minorities or vulnerable groups. 

Multidisciplinary Assessment of Crustacean Sentience

Crustacean sentience (the capacity of this group to experience emotions) has sparked a heated debate across multiple disciplines, particularly as it could impact several major sectors such as fisheries and aquaculture. The outdated argument that animals do not experience negative emotions (such as pain) because they lack conscience, has been proven wrong for vertebrates and some invertebrates (e.g. octopus), but remains controversial for crustaceans. There is evidence of criteria consistent with the idea of pain, as crustaceans have and activate nociceptive pathways, but there is no evidence of the neural pathways integrating the responses nor the demonstration of the awareness thereafter. This is partly due to the ‘dispersed’  central nervous system (CNS) these animals present, with multiple ganglia, but no ‘brain’ as a focal point. To overcome this, MACS aims to apply new technology to measure 9 simultaneous nerve signals (8 ganglia and the heart) to fully understand the nociceptive pathways and how are they integrated in crustaceans’ CNS. This approach will tackle the principle of triangulation by (1) The development of an electroencephalogram (EEG) to record the nervous system of commercially important crustacean species; (2) the characterization of pain and stress through physiological and molecular animal-based indicators; and (3) the evaluation of behaviour and its neurological integration pathway.  As such, this multidisciplinary study will only be possible through a combination of my crustacean stress physiology background, my supervisor’s knowledge of the central nervous system anatomy, and my second supervisor's expertise in aquatic species' EEG. The outcome of this fellowship will range from CNS studies to validate current industrial practices (during a non-academic placement), to socio-economic impacts involving the society's concern for animal welfare. The knowledge and skills gained from this project will allow me to become an independent researcher.

PrepApp: An Embodied Scenes approach for the teaching and learning of English prepositions

Prepositions play a critical role in communicating spatial relations that involve real-world physical entities (e.g., The keys are on the dresser) and abstract concepts (time after time), yet teaching their usage patterns can be tricky (Tyler, 2012). The research question addressed by this project deals with how we can teach prepositions in a systematic way. The purpose of this study is to address five scientific problems surrounding the teaching and learning of prepositions by bridging the divides between: (1) psychology and linguistics, (2) the laboratory and the real world, (3) native speakers and students, (4) educational professionals and accessible tools, and (5) disciplines by bridging a methodological gap via a novel theoretical framework. We can bridge these divides by implementing principles from cognitive psychology that tap into the mechanisms that scaffold thought processes. The main objective is to produce profiles for high frequency prepositions, to build lessons combining these profiles with an Embodied Scenes (ES) framework, and to test the lessons in the classroom. While new methods in preposition teaching are slow to be adopted, research is moving fast. An ES approach that is compatible with Cognitive Linguistics (CL) research may increase traction for preposition course materials. This study would provide data about real world behavior and provide an accessible tool for students.

Co-benefits and synergies between biodiversity conservation, poverty alleviation and climate change mitigation from a social-ecological systems perspective

CoBioPovCli addresses the question of how to conserve biodiversity, alleviate poverty, and mitigate climate change simultaneously, which are interrelated challenges that threaten human and environmental well-being. The importance of this topic is highlighted by the current context of the global COVID-19 pandemic and the Russia-Ukraine war, which have exacerbated these problems and their impacts on human and environmental well-being. The main gaps in this topic are: (1) lack of comprehensive data, especially on the dynamics of socio-ecological systems, (2) lack of integrated knowledge, and (3) lack of holistic approaches that consider co-benefits and synergies. CoBioPovCli aims to overcome the limitations and gaps in the current state-of-the-art by developing an integrated spatial planning approach that can achieve win-win synergies between biodiversity conservation, poverty alleviation, and climate change mitigation from a social-ecological systems perspective.  CoBioPovCli will use literature, models remote sensing data, and other data sources to construct and apply the spatial planning approach, based on case studies, spatial analysis and scenario simulation. CoBioPovCli will generate new knowledge, data and solutions that are conceptually novel, scientifically rigorous and policy-relevant. It will enhance our understanding of the multiple values of biodiversity and its contributions to human well-being under changing climatic conditions. It will provide evidence-based recommendations and best practices for promoting more integrated and sustainable approaches that benefit both people and the planet. CoBioPovCli will also enhance Europe’s scientific and technical capacity and excellence in the field of co-benefits and synergies between biodiversity conservation, poverty alleviation, and climate change mitigation, as well as contribute to Europe’s global leadership and influence in addressing these interlinked challenges.

Midlene fra PES-HORISONT-EU-PES Horisont Europa fordelt på år

Midlene fra PES-HORISONT-EU-PES Horisont Europa fordelt på fylker

Midlene fra PES-HORISONT-EU-PES Horisont Europa fordelt på fagområde

The project will prepare a proposal comprising a multinational consortium, consisting of companies, universities and R&D institutes in southern, central and northern Europe, enabling increased resilience and sustainability in international logistics. The project will have use-cases in three European regions:
1. Northern and Central Europe
2. The Iberian Peninsula
3. Northern Italy

The project coordinator is Fraunhofer EMI in Germany. 

Project partners are form Spain, Portugal, Italy, Germany, and Poland, in addition to Norway.

Norwegian partners are Marlo, SINTEF, and the Norwegian Road Administration.

Sustainable And Resilient Infrastructure and Logistics networks

Huntingtons disease (HD) is an untreatable inherited neurodegenerative disease causing motor and cognitive dysfunction and premature death, due to loss of specific neurons in the basal ganglia. Having access to the first transgenic rat model of HD, the pr esent project seeks to conduct the first in-depth survey of neural network changes in in the brains of presymptomatic and symptomatic animals. Combined expertise from the fields of neuroanatomy, genetics, and tomographic imaging will be employed to addres s questions about how HD affects the neural circuitry of the basal ganglia. We will first localize and quantify major structural brain changes occurring in conjunction with observed behavioral alterations, using contrast-enhanced in vitro high-resolution magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) in combination with immunocytochemistry and histological analysis. Secondly, we will characterize alterations occurring in the basal ganglia neural circuits using combined anterograde a nd retrograde axonal tracing techniques. Third, we will evaluate DWI as a diagnostic tool for detecting loss of axonal projections in this HD rat model. To facilitate comparison of multi-modal data across animals and experiments, a local coordinate system  for the basal ganglia will be constructed. This coordinate system will serve to normalize and co-register all data in a common framework, suitable for future sharing of data in a 3D brain atlas environment. The project will provide valuable anatomical da ta relevant for subsequent investigations of HD pathophysiology and evaluation of potential therapeutic interventions.

Structural characterization of neural network alterations in transgenic rat model of Huntington's disease

The focus of this application is to study how the extracellular matrix can influence transcapillary transport of water and protein. The aim of this specific project is to develop an in vitro model system of loose connective tissue which can work in close parallel to our in vivo experiments. The unifying concept of the separate projects is the hypothesis that extracellular matrix can have an «active» role on transcapillary transport: We have demonstrated that in inflammation and burn injury the tissues gen erate edema «actively» via a lowering of interstitial fluid pressure (Pif), in burn injury from -1 mmHg to as low as 150 mmHg, raising capillary net filtration pressure 150-300 times above control. In inflammation, we have demonstrated that the final and common step resulting in lowering of Pif is due to perturbation of the cellular beta-1-integrins receptors towards structural components in the extracellular matrix. Thus, contrary to the common notion, alterations in extracellular matrix rather than at t he capillary wall are responsible for the rapidly forming edema in acute inflammation. We will develop further a spheroid model system of connective tissue that allows studies on contribution of individual integrins to Pif, and their response to inflammat ory stimuli. Also the importance of paracrine mechanisms for tumor angiogenesis and growth and the role of the stroma in carcinoma growth will be studied using metods from cellular and molecular biology. Our observations offer new understanding of the dif ficulties of transport of cytostatic agents across the vasculature in cancers and at the same time provide new and mostly untested opportunities for facilitating such transcapillary transport in cancers. Our studies point towards the lowering of Pif as an  important and fundamental new pathophysiological mechanism also in septicaemia.

Role of stromal cells in normal and pathological tissue homeostasis

The olfactory coding mechanism responsible for reproductive behaviour have been thoroughly investigated in heliothine moths. This sub-family is particularly fascinating since the individuals communicate both within and across the species. Thus, the males possess receptor neurons detecting pheromones leading to attraction as well as receptor neurons detecting interspecific signals leading to avoidance. In the project presented here we intend to understand the relationship between connectivity patterns and olfactory-mediated behaviours by exploring the neural pathways from defined male specific glomeruli of the antennal lobe to higher integration centres in the brain of Helicoverpa assulta. The methods involve intracellular recordings from antennal-lobe pro jection neurons combined with fluorescent stainings for morphological characterization. By use of confocal microscopy and advanced visualization software the stained neurons will be reconstructed. By performing double labeling experiments, the projection patterns of physiologically/morphologically identified antennal lobe neurons will be compared with the the distribution patterns of relevant neuroactive substances.

Olfactory pathways connecting defined glomeruli of the macroglomerular complex to higher integration centres in the heliothine moth brain

We here present evidence that a novel class of genes encoding regulatory leukocytereceptors may be of clinical importance in autoimmune diseases elicited by environmental exposure to immunoadjuvants, in particular mineral oils. The evidence is based on th e structural identification of the rat Oia2-gene, a quantitative trait locus conferring susceptibility to autoimmune arthritis elicited in susceptible rat strains by exposure to small doses of mineral oil. We show that the trait is linked to a novel gene complex encoding regulatory leukocyte receptors expressed by professional antigen presenting cell. The functional role of these receptors, their cellular expression patterns, and the fact that the syntenic chromosome interval in humans is linked to autoim mune disease constitute evidence that the model is valid for the study of human autoimmune disease. We further argue that oil induced arthritis represent a searchlight model of a multifactorial trait where genes and environmental factors interact in the p recipitation of disease. We present project plans for 
- molecular and functional studies of these receptors and their interaction with the environmental agent in the rat model (collaboration with Centre for Molecular Medicine (CMM), Karolinska Institutet , Stockholm) 
- cDNA sequencing and single nucleotide polymorphism (SNP) analyses of a register of individuals with rheumatoid arthritis (collaboration with the Rheumatological Department at Diakonhjemmet Hospital and CMM, Stockholm) 
- cDNA sequencing of  selected individuals that have developed disease after exposure to hydraulic oils (collaboration with the National Institute of Occupational Health)

Oil induced autoimmune arthritis

Astrocytes are the most abundant cell type in the human cerebral cortex but the focus on these cell types have been far neglected. In the later years it has become apparent that they play important roles in the homeostasis of the brain and evidence now al so suggests that they are essential components at the blood brain barrier (BBB). In a very recent unpublished study, we have shown that the lactate transporter, monocarboxylate transporter 4 (MCT4) is densely concentrated in the part of the astrocyte plas ma membrane that abuts on the brain microvessels (the perivascular membrane). Considering the localization and characteristics of this transporter suggests that MCT4 may be a key mediator of excess lactate efflux from the brain. This is not only important  for normal brain function but perhaps even more so during and following ischemia (stroke) and hypoxia when large amounts of lactate is produced. This future project will investigate the interplay of the different components of the blood brain barrier (BB B). Interactive proteins between astrocyte, basal lamina, endothel and pericytes will be studied as well as the actual anchoring proteins of MCT4. Such information would give key findings of components that may be a part of the disruption of the BBB follo wing pathological conditions such as stroke. It could also give us a greater understanding why lactate, a product of anaerobic metabolism, can accumulate to lethal high levels in the brain. Another key finding from the recent MCT4 study suggests that lact ate may act as a signaling molecule to couple local brain blood flow and neuronal activity in the normal brain. We wish to persue this finding in a collaboration with Professor Lauritzen (University of Copenhagen, Denmark) to investigate the physiological  role of lactate to regulate blood flow in an in vivo model where neurons can be stimulated and blood flow measured simultaneously.

Astrocytes - guardians of neuroprotection

A considerable challenge in neuroscientific research is to explain processes at the systems level in terms of mechanisms at cellular and molecular levels. The retina serves as an ideal model system amenable to experimental approaches that directly aim to bridge this gap. With respect to the sensory processing taking place in the retina, a fundamental challenge is to understand how specific molecular and cellular mechanisms are adapted to the signal processing taking place in identified synaptic circuits. The principal objective of the current project is to understand, at a molecular and microphysiological level, the integrative dynamics of a neuronal network that plays a pivotal role for vision under dark-adapted conditions. To achieve this goal, we will use a combination of experimental (multielectrode patch-clamp, dynamic clamp, capacitance measurements, ultrafast drug application, morphological single-cell reconstruction) and theoretical (computer simulations of ion channels, single cells and small net works) investigations of bipolar cells and amacrine cells in the rod pathway of the retina. A very important technical aspect of the project is to aggressively extend our ability to perform electrophysiological recordings from ever smaller neuronal proces ses by combining infrared videomicroscopy with fluorescence imaging. First, we aim to increase our understanding the synaptic transmission between rod bipolar cells and AII and how diabetic hyperglycemia might change the functional properties of the invol ved AMPA receptors. Second, we aim to increase our understanding of the functional properties and consequences of electrical coupling between AII amacrine cells. Finally, we aim to increase our understanding of the role of voltage-gated ion currents and G ABAergic feedback in shaping the response properties of rod bipolar cells. A successfull project will increase our understanding of the dynamics of a synaptic microcircuit of fundamental importance for human vision.

Dynamics of synaptic transmission in the rod pathway of the retina

Metabolic scaling is a widely recognised problem in biology. The underlying causes for the disproportionate relationship between the metabolic rate of an organism and its body size have long puzzled scientists, and continue to be controversial. In recent years this fascinating subject has been treated more than 25 times in Nature, Science and PNAS. However, the editorial (Hoppeler & Weibel, J Exp Biol, May 2005) summarises the state-of-the-art in the monograph on metabolic scaling as: ´There is only one c onsensus: There is scaling, but how and why?´ Our hypothesis is that scaling in teleost fishes is primarily demand-driven based on age-related control of mitochondrial metabolism and density in the differentiating tissues.

Most studies have simply remode led existing data, rather than investigating the underlying causes of metabolic scaling. The current proposal represents a new approach to the problem, and extends the results of Finn et al. (2002) and the solid pilot study of Finn and Cruz (2003). We aim  to test our hypothesis that there is a single principle - but many exponents - underlying the cause of mass-metabolic scaling. We will do this by quantifying both the volume fractions of red and white muscle, and the change in mitochondrial density with development in these tissues (WP1). In WP2 we will determine intrinsic metabolic rates and substrate preferences of the red and white muscle mitochondria under varying substrate and temperature conditions. In WP3, gene manipulation experiments will be att empted in order to demonstrate the cause and effect relationship that altering the aerobic basis of muscle metabolism has on metabolic scaling.

The project includes salary for the principal investigator, and is designed to attract students with diverse i nterests at the MSc and PhD levels.

Metabolic scaling in teleosts

Recent studies, including ours, have shown that the invasive behaviour of cancer cells is not solely due to mechanisms intrinsic to the individual tumour cell. Genetic changes of individual cells in a specific tissue are not sufficient for invasive cancer  to develop. Rather, there is a vivid crosstalk between the transformed cells and normal surrounding cells that affects cancer cell growth and invasion.

The project tests the hypothesis that in addition to genetic changes harboured by transformed oral ke ratinocytes, pro-invasive signals from activated stromal fibroblasts and abnormal communication between cancer cells and normal neighbouring keratinocytes critically influence progression of oral neoplasia, due to their effects on survival and expansion o f oral cancer stem cells.

The role that normal oral keratinocytes and fibroblasts have on clonal expansion and survival of cancer cells will be investigated on in vitro and in vivo human tissue-based experimental models that allow such cell-to-cell inter actions. In vitro three-dimensional models of normal and neoplastic human oral mucosa are well established in our laboratory. Advanced three-dimensional confrontation models in which clones of green fluorescent protein / alkaline phosphatase marked cancer  cells develop surrounded  by normal oral cells are currently engineered in our laboratory.

A small subset of cells with stem properties has been isolated from oral squamous cell carcinomas (OSCC) derived cell lines by prof. Ian Mackenzie's research grou p at the Centre for Molecular Science, University of London. In collaboration with this research group and the local Stem Cell Research Group at the University of Bergen, we are currently isolating and characterising putative stem cell populations from fr esh tissues (normal human oral mucosa and OSCC), as well as from OSCC- and normal oral mucosa-derived cell lines. Our plan is to further use these putative stem cell populations in confrontation models.

The role of normal neighbouring keratinocytes and fibroblasts on clonal expansion of oral cancer (stem) cells

A major challenge in neuroscience is to understand the mechanisms of neuronal computation, much of which is carried out by electrical signals generated by ion channels in the cell membrane. Within the last decade, advances in patch-clamp and imaging techn iques have extended our knowledge of such mechanisms into the smaller, sub-cellular domains. Accumulating evidence suggests that thin dendritic branches, such as the oblique dendrites and tufts of cortical pyramidal neurons, can execute local integration and "binary computations", due to the presence of dendritic ion channels. Furthermore, two recent publications showed that axons in the mammalian cerebral cortex transmit not only "all-no-none" action potentials but also subthreshold analogue signals, whi ch can strongly modulate synaptic output from axon terminals. These novel mechanisms are likely to greatly enhance the computational power of our nervous system. However, our understanding of these processes has been limited by difficulties to obtain elec trical recordings directly from thin neuronal structures. In this project, we will use fluorescent video microscopy-guided patch-clamp recording from thin dendrites and axons in the cortex to study their electrical signaling mechanisms. The project will f irst focus on establishing new methods for patch-clamp recording (loose-patch, cell-attached and, when possible, whole-cell recording) from thin neuronal structures. Next, we will study (1) the mechanisms regulating sub-threshold axonal propagation, (2) t he ionic mechanisms regulating local spikes in thin dendritic branches, and (3) the contribution of three types of K+ channels (BK, SK and KCNQ/Kv7/M channels) to the excitability of the apical dendrite of cortical pyramidal neurons. Computational simulat ions, using detailed, conductance-based, multi-compartmental models of pyramidal neurons, will be performed in parallel with the experiments.

Electrical signaling in thin dendrites and axons in the cortex

Modern brain imaging methods have contributed enormously to contemporary knowledge about the particular brain systems involved in specific cognitive functions. Unfortunately, mechanistic insights have lagged behind, largely because brain mapping in humans  lacks the spatial resolution required to study brain activity dynamically at the level of individual neurons and neuronal circuits. The aim of the present project is to use state-of-the-art viral transfection technology to image brain function at the res olution of microcircuits, cell types and individual neurons in behaving animals during encoding and retrieval of memory. We shall use recently developed viral vectors for introducing molecular markers into specific cell types in the hippocampus and entorh inal cortex in vitro and in vivo. This approach will allow us to determine how newborn neurons are integrated into the cellular network of the dentate gyrus, and has the potential to disclose the locus and function of synaptic plasticity in remapping and coordinate transformations in grid cells of the entorhinal cortex and place cells of the hippocampus.

Functions of hippocampus and entorhinal cortex studied with viral vectors

More than 30 years of research have pointed to the hippocampus as a key component of the brain's circuit for spatial representation. Although place-specific firing is undoubtedly the most conspicuous behavioural correlate of hippocampal principal neurons,  hippocampal neurons also respond to a variety of non-spatial sensory inputs, and they can alternate between multiple representations of the same location, suggesting that the spatial signal itself originates from outside the hippocampus. We have shown th at the medial entorhinal cortex, one synapse upstream of the hippocampus, contains a metric representation of current location. Self-location is represented in this area by a network of spatially tuned grid cells, whose firing locations form a periodic tr iangular pattern tiling the entire environment of the animal, resembling the cross points of graph paper except that the unit is triangular and not square. Grid cells have a number of properties implying them as part of the brain's coordinate system for s elf-motion based metric calculation. The aim of this proposal is to establish the organization of the microcircuit by which spatial location is computed from directional and distance-related inputs within the microcircuit of diverse cell types in the medi al entorhinal cortex, and to determine how spatial representations in entorhinal grid cells interact with cells in other cortical brain regions such as the hippocampus. The representation of spatial location has appeared as one of the first cognitive func tions to be understood in mechanistic detail, and we shall to use the opportunities emerging from our recent discoveries to understand general principles of computation in cortical microcircuits. The results will ultimately benefit the development of tool s for the diagnosis and treatment of Alzheimer's disease, which commonly begins in just the brain area that contains the grid cells.

Entorhinal grid cells and hippocampal memory

The rationale for organizing this type of workshop is that the ion content in cells is strongly related to the cellular physiology. On a broad basis we will discuss the interactions between compatible organic solutes and inorganic ions with respect to cel lular levels, transport, and availability of ions in the environment. We will pay special attention to osmotic properties of osmolytes like Na+, Mg2+, NO3- and DMS/DMSP. For years the focus of osmoadaptation has been on microorganisms exposed to osmolalit y changes in their natural habitat. Any osmotic stress is followed by activity changes in enzyme activity and proteins related to transport. External osmotic pressure, turgor pressure and internal osmolality are key elements in understanding the physiolog y of cells. More specific knowledge of how microorganisms sense changing osmolality and the mediation of signals for gene expression and enzyme activation is rapidly emerging. 
Our recent studies of elemental composition of marine bacteria have shown that  Na+ and Mg2+ have a key role in the physiology of native marine bacteria. Since native marine bacteria for periods are under carbon/energy limitation, the apparent change between organic osmolytes and ions seem to offer some interesting signatures for av ailability of organic carbon. Any such signatures would greatly add to our understanding of large scale transfer of carbon in the marine environment.
Apart from the points given above recent reports of bacteria living in narrow gradients keeping high inte rnal concentrations of ions like NO3- is of considerable interest. The ion balance and internal charge balance of these organisms is still an open question.
Environmental effects of cells with high levels and release of DMS/DMSP have got much attention fo r their influence on cloud formation and acid rain, and algae/bacteria are in this respect important.

International workshop on ions in bacteria

The Scandinavian Physiological Society will hold its Congress for 2007 in Oslo from the 10th to the 12th of August. Here we apply for financial support to arrange this Congress.

Scandinavian Physiological Society's Congress 2007

Primary gliomas represent one of the greatest challenges in neuro-oncology. Recent studies have identified so-called ?cancer stem cells? in several cancers. These cells have the capacity to proliferate and establish tumors in laboratory animals after inje ction of only a small number of cells. Moreover, cancer stem cells are resistant to radiation- and chemotherapy, which may explain why many tumors regress significantly with current treatment regimens, only to recur later with more malignant properties. A  major research question in our laboratory is to identify the nature and origin of the cancer stem cell. Do cancer stem cells originate from more differentiated cells that become mutated and acquire stem cell-like properties? Or, do they originate from th e normal neural stem cell population present in the brain that has undergone oncogenic transformation? Here we propose to characterize the cancer stem cell in glioblastoma and explore whether and how such a normal-to-cancer stem cell conversion occurs..A second major research theme is to identify the key molecular events that drive invasive and angiogenic properties of cancer and cancer stem cells. This includes studies on the mechanisms required to establish an invasive or angiogenic phenotype. Using adv anced animal models, we will compare the protein expression profiles of a highly invasive, non-angiogenic stem cell like tumour to less invasive, highly angiogenic tumor phenotypes. The overall aim of our research is to identify basic processes involved i n tumour formation and characterize key molecules involved in invasion and angiogenesis. This will allow the development of more effective and targeted brain tumour therapies.

New therapeutic principles and biological mechanisms related to brain tumour cell invasion and angiogenesis

Parkinson's disease is characterised by death of dopamine containing neurons in the substantia nigra. Long term levo-dopa treatment has severe side effects and is potentially toxic for neurons. The need for alternative treatments in Parkinson's disease is  urgent. To accomplish this, further research on the link between dopamine and glutamate transmission in Parkinson's disease is needed. By way of electron microscopical immunocytochemistry and electrophysiological methods we will use an experimental rat m odel of Parkinson's disease to study the following questions: 1) Do nigro-striatal dopaminergic neurons release glutamate from separate excitatory types of synapses? 2) Are the glutamatergic synapses belonging to the nigro-striatal dopaminergic projection  affected in an experimental model of Parkinson's 
3) Are markers of glutamate exocytosis present in striatal astrocytes? 4) Is the glutamatergic signalling system in striatal astrocytes altered in experimental models of Parkinson's disease? 5) Are aspart ate and NMDA receptors involved in the pathogenetic morphological alterations in Parkinson's disease

The role of excitatory amino acid in Parkinson's disease

A major challenge in neuroscience is to explain behaviour in terms of molecular, cellular and neuronal network mechanisms. We will study mechanisms of the medial temporal lobe memory system by in vivo recording of hippocampal single unit and neuronal netw ork activity (EEG) in freely mowing rats and mice. By combining in vivo electrophysiology and behavioural studies with pharmacology (selective ion channel blockers) and genetic manipulations (transgenic mice, rats injected with lentiviral vectors) we will  bridge the gap between the molecular-cellular and network-behavioural levels of investigation. In this project we will focus on (1) the M/Kv7 and SK type potassium channels in hippocampal neuronal activity and memory, (2) the function of back-propagating  action potentials during normal behaviour, and (3) an animal model of Alzheimer's disease. In additon, it is a strategic goal to establish unit recording from behaving animals at the Univeristy of Oslo, where this method is currently not available to neu roscience groups, including the Centre for Molecular Biology and Neuroscience. It is also a strategic goal to establish in vivo unit recording from freely moving mice, which has previously not been performed in Norway, but wil open a wealth of possibiliti es for studying strains of transgenic mice e.g. produced by the Norwegian Transgenic Centre (NTC, Oslo) and the National Centre for Stem Cell Research in Oslo.

Molecular and cellular mechanisms of the hippocampal memory system studied by in vivo recording in behaving animals

In order to better understand and control how neurons work we need more knowledge about thin, unmyelinated axons because:
*	They are the most common, but yet the least studied axonal type in the mammalian cortex.
*	They are the most excitable part of the neuron and are, therefore, very important for control neuronal activity.
*	Both theory and experiments suggest that they have properties that are different from other axons.

During the last years, we have developed methods for direct axonal recordings th at have opened the possibility to investigate such axons in more detail than before. Using these methods we and other groups have shown that these axons have unique properties. They have, for example, specific membrane currents that control their excitabi lity specifically during high frequencies. Such knowledge gives the opportunity to develop treatment strategies that specifically targets neuronal hyperactivity, which is a problem of great clinical significance.
Continuation of the research to find out m ore about the spike generation and conduction processes is therefore important in order to fill the significant gap in the knowledge about how neurons work. By studying axonal properties, we can target their specific mechanisms and develop pharmacological  methods to control excitability which is of great interest in the treatment of, for example, epilepsies and spasticity.

The properties of thin, unmyelinated axons in mammalian brain

While most vertebrates die within minutes of anoxia (no oxygen), a few species can tolerate anoxia about 1000 times longer. These include the crucian carp (Carassius carassius, No: karuss), a common fish in Norway, and some turtles.
  Anoxia and ischemia related diseases are the major killers in the industrialized world, and a main motivator for our research is to find out how evolution repeatedly has solved the problem of anoxic survival - something medical science has failed to do.
 Our studies range fr om neural and cardiovascular physiology to gene expression. We now aim to follow up on three particularly hot trails that have recently emerged from our research. Our finding that the crucian carp has the ability to remodel its gills during hypoxia in ord er to boost oxygen uptake clearly deserves further studies. This is the first example of an adaptive and reversible gross-morphological change in a vertebrate respiratory organ. Moreover, we have just showed that the crucian carp heart continues to functi on at full speed even after 5 days without any oxygen in vivo. No other vertebrate heart comes close to such a performance during anoxia, and this finding urgently calls for more experiments. Finally, we have recenty found that the crucian carp is doing t he "impossible": it forms new cells in anoxia although a key step in DNA synthesis is thought to be oxygen dependent. In this final project, we take a broad approach. We will study both cell proliferation and synaptic plasticity by examining the expressio n of key regulatory factors in time and space. We will use the FRIBIOFYS grant for the salary of a PhD student and a researcher to run these projects. We also aim to attach MSc students  to parts of the projects.

Surviving without oxygen - from heart function to DNA replication

We are searching to uncover the neuronal network involved in chemosensory coding and appetitive learning in insects, using moths of the subfamily Heliothinae as model organisms. The focus in the present project is to characterise physiologically and morph ologically neurones in the primary and the higher olfactory centres of the brain, which form the network processing plant odour information. The methods involve long-lasting extracellular recordings linked to gas chromatography, in addition to ongoing int racellular recordings combined with fluorescent staining, confocal microscopy and three-dimensional reconstruction of the neurones. The present study will provide information about responses to biologically relevant plant odorants, from which types of fun ctionally identified receptor neurones they receive information, and how the information is processed. By comparing the physiological data of the long-lasting extracellular and the short-lasting intracellular recordings we can determine the functional org anisation of the olfactory pathways. Precise determination of the dendrite arborisations and the axon projections in the different neuropil structures of the brain will be made by placing the reconstructed neurones into an averaged brain atlas. The result s will also contribute to the understanding of the neuronal mechanism underlying the behaviour of these important pest insects.

NEURONES FORMING FUNCTIONAL NETWORKS IN THE MOTH BRAIN

Heart failure, the final outcome of many cardiovascular disorders, is a major cause of morbidity and mortality in the Western Hemisphere. Indeed, the incidence and prevalence of heart failure in the Western Hemisphere are increasing due to altered demogra phics with increased proportion of elderly, as well as increased survival of myocardial infarction. Despite implementation of several new treatment modalities during the last 20 years, heart failure is still a progressive and ominous disease, indicating t hat important pathogenetic mechanisms remain unmodified by the most current treatment. Development of heart failure is characterized by several alterations of myocardial structure including dilatation of the ventricular cavities, cardiac myocyte hypertrop hy and fibrosis. These important structural alterations of the heart, often referred to as cardiac remodeling, have recently been emphasized in the new recommendations of the American College of Cardiology/American Heart Association Task Force for the eva luation and management of chronic heart failure in the adult. These new approaches to the classification of heart failure, which are meant to complement the New York Heart Association (NYHA) functional classification, stratifies patients according to risk  factors for developing heart failure, and to the absence or presence of structural alterations of the heart. Although, recent research has provided substantial new insights into the mechanisms of myocardial hypertrophy and fibrosis, many of the nodal poi nts that orchestrate these structural alterations still remain to be identified in order to develop new and more effective therapeutic modalities. In this respect, the aim of the present research proposal is to provide novel insights into the G protein-co upled receptor kinases (GRK), i.e. a family of kinases that are important proximal modulators of many receptor-controlled signal transduction pathways involved in regulation of myocardial function and growth.

Molecular Pathogenetic Mechanisms of Heart Failure - Dissecting GRK Function in The Heart

The honey bee is a key neurobiological model for understanding learning and memory formation. As a highly social invertebrate, moreover, the bee provides unique opportunities for cutting-edge research on aging and frailty because it opens up the interface  between the individual and the social environment. 
   Our group at UMB's Department of Animal and Aquacultural Sciences has over the last five years contributed to a deeper understanding of the regulation of honey bee lifespan. We have, e.g., shown that  aging in worker bees is not a clear-cut function of chronological age. This is because aging can be controlled by social signals through a feedback pathway that involves the systemic hormone juvenile hormone and the gene vitellogenin. Recently, we starte d to investigate whether oxidative brain damage, a hallmark of aging, can be affected by social signals as well. Our preliminary data, obtained from immunohistochemical staining of 150 brains from 8-200 day-old workers, suggests that this is indeed the ca se. The proposal presented here outlines how we intend to move forward in our work to understand the pathology and social regulation of honey bee brain aging.
   Explicitly, we want to take advantage of the fact that we are at the research forefront in th e field of honey bee longevity regulation; mastering a broad range of key techniques including brain immunohistochemistry, RNA interference methodology, immuno- and ligand-blot procedures. From this foundation, we will first dissect the pathology of bee b rain aging in collaboration with Dr. Gimsa (Sub-goal 1). Next, together with Dr. Scheiner, who is an expert in the use of the bee as a neurobiological model, we will establish how brain aging affects the bee's sensory sensitivity and cognitive abilities ( Sub-goal 2). Finally, we will determine the extent of which the pathologies mapped under sub-goals 1 and 2 can be controlled, and possibly reversed, by social signals (Sub-goal 3).

Dissecting the physiological, sensory, cognitive, and social dynamic features of cellular aging in the honey bee worker brain

Capillaries are highly permeable to water and small solutes but very restrictive towards protein. This arrangement is necessary to maintain fluid equilibrium between plasma and tissue. There is a slow transfer of protein to supply tissues with e.g. import ant bioactive molecules. How the transport of fluid and molecules takes place is, surprisingly, still a controversial issue.
With the present project I aim to investigate how transcapillary transport is accomplished. First, I focus on macromolecular trans port: Is it by vesicular transport (transcytosis) or across pores? The transport characteristics of genetically modified mice that lack endothelial caveolae, and thus are incapable of transcytosis will be studied. Furthermore, specific macromolecular (alb umin) transcytotic uptake will be blocked by using a specific antibody. Second, I focus on fluid and small solute transport in a clinical situation (peritoneal dialysis, PD): Is fluid transport from peritoneum by way of lymphatics or by capillary reabsorp tion (Starling equilibrium)? To adress this issue I will measure the gradients that govern the Starling equilibrium in a chronic PD model. Why does patients on long-term PD develop morphological and functional changes eventually leading to change of dialy sis therapy? To adress whether this is related to the low-grade inflammation induced by PD, a chronic PD rat model will be employed and proinflammatory cytokines will be measured in the peritoneal tissues. Furthermore, to adress the same issue, an antiinf lammatory substance (heparin) will be added to the fluid during PD in rats while assessing the transport characteristics.
This project has a translational character with important implications for drug delivery and states of perturbed microvascular permea bility. It also may lead to better prescription of dialysis dose and understanding of why patients on chronic peritoneal dialysis develop morphological and functional changes.

Mechanisms for transcapillary transport-from molecules to clinical application

Glutamine, the most abundant amino acid in plasma and cerebrospinal fluid, is important for many metabolic processes, e.g. biosynthesis of amino acids, purines and pyrimidines. Glutamine is a major N- and C-donor involved in inter-organ and inter-cellular  shuttling of metabolites. It is a signaling molecule as transport into cells has direct effects on cell function. We have molecularly characterized a family of amino acid transporters with high affinity for glutamine. Transport of glutamine by SN1 and SN 2 is electroneutral and bidirectional due to coupling to Na+ in symport and H+ in antiport. In contrast, SAT1 and SAT2, that are unable to bind H+, carry unidirectional transport accumulating glutamine inside the cells. SN1 is regulated through several me chanisms: through proton action directly on the SN1 protein, at the protein synthesis level, and by stabilization of mRNA via the pH-response element. The level of SN1 protein is increased in glioblastoma multiforme, and SN1-mediated glutamine transport i nto anaplastic cells may be a limiting factor for growth and metastatic ability. We therefore want to study regulation of SN1 and SN2 in normal cells and in tumors. We want to explore intracellular modifying proteins/enzymes acting on SN1 or SN2 and poten tial linkage to oncogenes. Regulation by phosphorylation and the target residues will be characterized, before site-directed mutagenesis and expression in heterologous systems is performed to map the effects on expression levels, membrane trafficking and functional activity. Pathways of controlled protein degradation will be studied in normal, neoplastic and apoptotic cells. Additional regulatory mechanisms may be revealed in SN1 and SN2-deficient mice. The project aims to give insight into cell growth an d development of neoplasia. The data may explain functional changes in the tumor surroundings, such as altered synaptic transmission in the vicinity of CNS tumors leading to development of novel therapeutic schemes.

FUNCTIONAL SIGNIFICANCE OF INTRACELLULAR REGULATION OF GLUTAMINE TRANSPORTERS IN NORMAL AND MALIGNANT CELLS

Neural cell transplantation for repair of CNS lesions is one of the most exciting new avenues in the field of Neuroscience. With regard to spinal cord injuries (SCI), however, neuronal replacement has received relatively little attention because SCI has b een thought  to be a "white matter" problem (oligodendrocyte inhibition of axon regrowth). However, recent evidence indicates that loss of gray matter also causes severe motor deficits, suggesting that restoration of the spinal gray matter may also play a n important role in recovery. Regardless of the mode of SCI repair, a crucial question is whether regenerated axons or transplanted cells have the proper synaptic connections to ensure functional recovery. This has hardly been addressed in international r esearch into spinal cord injury. In particular, no studies have used electrophysiological methods to address whether stem cells integrate into spinal neural networks.

To address this issue we will use our newly developed xenotypic in vivo model (regenera ting chicken embryo spinal cord) which stimulates human hematopoietic stem cells (hHSCs) to differentiate into neurons. Being the first to employ electrophysiological approaches to show that human stem cell-derived neurons display synaptic activity in viv o (Sigurjonsson et al, 2005), we have now a unique opportunity to maintain a leading position in this field internationally. To determine whether and with what specificity the hHSC-derived neurons functionally integrate into spinal networks, we will analy ze their synaptic connectivity using electrophysiological recording. Specifically, we will assess synaptic inputs from peripheral sensory afferents and from supraspinal descending pathways, both major sources of inputs that control movement. The proposed research will take place in Professor Joel Glover's group at the University of Oslo. The outcome of the proposed research will be particularly important for future use of stem cells in reparative medicine.

Stem cells from adult humans develop into neurons in the chicken embryo spinal cord but are they functionally integrated in neural networks?

The project aims at developing nanocrystals or  Quantum dot (QD) technology for in vivo use in general, and for tracking single molecules in particular. Quantum dots emit fluorescence and have emission spectra that are orders of magnitude more intense tha n conventional dyes. An antibody is usually needed to ensure specific binding of the QD. To date however, the use of QDs in vivo has been limited since the conjugation of an antibody to the QD makes it relatively large. Project 1: Is aimed at the adaptati on of QDs. QDs conjugated to [a]-bungarotoxin to label acetylcholine receptors (AChRs) we will use the technology to track single molecules in the synapse, in order to elucidate basic mechanism for synapse formation, synapse maintenance, and synaptic comp etition. Project 2: Rapsyn is a synapse protein that binds AChRs and it is essential for synapse formation. We plan to clone dominant negative forms of rapsyn into plasmids and overexpress them in muscle cells by single cell injection of the plasmids. We will use modified QDs to track the fate of rapsyn and AChRs after transfection to investigate the effect of dominant negative forms of rapsyn at the adult NMJ. Project 3: Competition between neural inputs is one of the fundamental problems in neurobiology . This competition between active and less active synapses be recapitulated adult animals by the formation of ectopic synapses or by the partial blockade of single synapses. In both cases a "winning" and a "losing"synapse can be studied, and the receptor dynamics investigated using QDs. This will allow us to study early events in clusters in membrane regions where the ultimate fate of the clusters will be known.

Adaptation of nanocrystals for in vivo use in tracking of single molecules at the neuromuscular junction

Since our original publications in 1996 showing that malignant plasma cells (MM cells) usually express both HGF and its receptor c-Met, a growing number of reports have implicated HGF/c-Met in the biology of MM. For instance, high levels of HGF in serum o f an MM patient predict a bad prognosis and correlate with increased angiogenesis in the bone marrow. HGF supports growth of MM cells, often in an autocrine way. HGF stimulates adhesion of MM cells to fibronectin and promotes MM cell migration. HGF is not  expressed by normal plasma cells, but is an aberrantly expressed gene in over 50 % of cases with MGUS, the premalignancy often preceding MM. MM is now subclassified in 8 groups based on molecular ethiology and on differential expression of cyclin-D. Inte restingly, the HGF gene is expressed in 4 of these groups and largely silent in the remaining 4, whereas c-Met is always expressed. In 2 of the groups where HGF is highly expressed, the primary oncogenic event leading to malignancy is unknown. We hypothes ise that HGF expression is a basic oncogenic event in the cases of MM where it is expressed, and that it induces expression of cyclin-D1 and other molecules important for cell growth. Consequently, we think that HGF/c-Met will be an important therapeutic target in MM. 
To elucidate this we will:
1) examine the HGF gene in MM cells by interphase FISH, Southern blots and direct sequencing to detect gene aberrations; 
2) map molecular targets downstream of c-Met by gene expression profiling;
3) treat mice wi th MM with a novel pharmacological inhibitor of c-Met; and
4) examine expression of HGF and c-Met (including activated c-Met) in biopsies from patients with MM.
The project is collaboration with a leading MM research center in the US, UAMS in Little Rock,  Arkansas. Erming Tian, BS MBA, Laboratory Director in Dr. John Shaughnessy's at UAMS, wants to do a Ph.D. at NTNU and will work in Trondheim for longer periods.

Hepatocyte Growth Factor in the Pathogenesis of Multiple Myeloma

Excitatory amino acids play dual roles in the brain: they are physiological transmitters
but have the potential to damage brain tissue. The same may be true for lactate, an
important intermediate in cell metabolism. The project will study the roles of exc itatory
amino acids and lactate transport in normal synaptic transmission and test whether they
are involved in the development of brain diseases, such as epilepsy and stroke. To our disposal are knock-out mice for synapsins and a vesicular glutamate tran sporter (VGLUT3). The study will make use of the intact rat brain, in vitro brain slice preparations and experimental models for stroke, as well as human epileptic brain tissue (removed as part of surgical treatment for epilepsy). In particular, by using immunocytochemical methods, including quantitative electron microscopic immunogold cytochemistry, and electrophysiological techniques (international collaboration), the project will seek to answer the following questions: What are the mechanisms underlyin g the propensity for seizures in synapsin knock-out mice, despite their impaired synaptic function? May MCT2 and MCT4 activity modulate excitatory amino acid transmission? Does glutamate contribute to signalling at the neuromuscular junction, and what is the role of VGLUT3 at this site? Is aspartate involved in the pathogenesis of epilepsy? Are MCTs involved in the pathogenesis of epilepsy and stroke? What are the cellular and molecular mechanisms of action of the widely used anti-epileptic drug valproate ? The knowledge gained will provide new insight in disease mechanisms and may lead to new therapeutic and diagnostic measures in neurology.


Glutamate and lactate: Jason-faced actors in neurology

Prevention and cure of neurological diseases are hampered by a lack of knowledge of
the underlying pathogenetic mechanisms which involve a complex system of
transporter proteins. The primary objective of this proposal is to uncover how
transporters limit activation of brain neurotransmitter receptors. To achieve this, it is
not sufficient to generate qualitative data on transporter and receptor localizations. It
is necessary to determine the numbers of the various protein molecules at different
locations within and around synapses. Then this information must be analyzed using
super computer simulation of neurotransmitter diffusion in dynamic 3-D models of
cubes of brain tissue. The models must take into account protein densities,
localizations, affinities , and other relevant properties like ion channel conductances
and associated water transport. We will begin the development of these advanced models, and we will also provide the quantitative data (molecules per square micrometer membrane) 
needed to mode l the roles of all the transporter proteins with affinity for 
glutamate and GABA. One transgenic mouse line will be produced to address an important questions related to the model: the functional importance of glutamate transporter EAAT2 in synaptic
term inals. This project combines expertise in computer simulation, brain
ultrastructure, membrane protein purification, molecular biology, water transport and
electrophysiology in order to achieve the ambitious goal.

Dynamic 3-D modelling of the synaptic environment: The roles of transporters in controlling receptor activation and water transport

Atherosclerosis is our major cause of morbidity and mortality, causing cerebral stroke, myocardial infarction, lower extremity gangrene, renal infarctions etc. Atherosclerosis is a chronic process involving both innate and adaptive immunity in its develop ment, and is a subject for attempts of immunomodulation in several research centers throughout the world. 
    In ischemic heart disease cardiomyocytes die by necrosis or apoptosis, or reversible symptoms such as arrhythmias or myocardial dysfunction are observed. To salvage ischemic myocardium revascularisation is essential, but may cause reperfusion injury. The pathophysiology of reperfusion injury involves an inflammatory process. Short episodes of ischemia and reperfusion prior to a sustained ischemic  event, termed ischemic preconditioning, increases the tolerance to ischemia in all organs investigated. Preconditioning signals its protection through activation of innate immunity. In depth analysis of the role of innate and acquired immunity in this co ntext may lead to development of immunomodulatory therapies.
    Innate immunity is a non-spesific line of defence responsible for containing microrganisms at the site of entrance, mediated by a host of cells producing cytokines and activating proteolytic  cascade systems in response to pathogen associated molecular patterns. Pattern-recognition receptors such as toll-like receptors are bridges between innate and acquired immunity, as their binding to microbial ligands mature dendritic cells  and trigger a ntigen-specific adaptive immune responses. Toll-like receptors signal to the transcription factor nuclear factor kappa B, which we know is important for evoking preconditioning. This program explores a possible role for toll-like receptors, pattern recogn ition receptor ligands, and activation of myeloid and lymphoid cells in evoking myocardial protection. The target is to establish an immunomodulatory therapy to evoke protection against acute myocardial ischemia.

Innate and acquired immunity in myocardial adaptation to ischemia - possible therapeutic gains?

Glioblastoma multiforme is the most malignant of the primary brain tumors with grave prognosis.  Recent studies have identified so-called "cancer stem cells" in glioblastomas and other tumors.  These cells have the capacity to proliferate and establish tu mors in laboratory animals after injection of only a small number of cells.  Furthermore, cancer stem cells are resistant to radiation- and chemotherapy, which may explain why many tumors regress significantly with current treatment regimens, only to recu r later with more malignant properties.  What is the origin of these cancer stem cells?  Do they originate from more differentiated cancer cells that acquire stem cell-like properties?  Or, do they originate from the normal neural stem cell population pre sent in the brain?  Recent studies indicate that endogenous neural stem cells are attracted in large numbers to experimental glioma in mouse brain tumor models, and inter-mix with glioma cells.  This raises the possibility that tumor-causing genes may end  up in normal stem cells, transforming them into ?cancer stem cells?, which then drives cancer growth.  We propose to explore whether such a normal-to-cancer stem cell conversion occurs.  Determining the origins of cancer stem cells will facilitate develo pment of more effective and targeted brain tumor therapies.

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