Lundbeck Foundation Center for Biomembranes in Nanomedicine > Research

The Molecular Neuropharmacology Laborary consists of ~25 people who study the molecular, cellular and genetic processes underlying synaptic signal transmission and how these processes can be modulated by drugs. We focus primarily on the presynaptic transporters for the biogenic amine transmitters, dopamine, norepinephrine and serotonin. These transporters belong to the family of Neurotransmitter:Sodium:Symporters (NSS) and tightly control the availability of the biogenic amines in the synaptic cleft. The transporters are targets for pharmaceuticals used against depression, anxiety disorders and ADHD as well as for drugs of abuse such as cocaine and amphetamines. In addition, we have a major interest in 'scaffolding' proteins such as PICK1 that, via specific protein-protein interactions and protein-lipid interactions, organize neurotransmitter transporters and receptors into desired cellular microdomains and multiprotein signaling complexes. In our research we employ a broad spectrum of in vitro and in vivo techniques ranging from advance biophysical techniques to genetic mouse models. In particular, the group has strong expertise in structural and pharmacological analyses of neurotransmitter receptors and transporters, expression and purification of membrane proteins and scaffolding proteins, characterization of protein-protein interactions, fluorescence spectrocopy, knock-in and knock-out mouse models and advanced bioimaging techniques. The group is supported by grants from the Lundbeck Foundation, Danish Research Councils, NIH U.S.A., University of Copenhagen Program of Excellence, the EU and the Novo Nordisk Foundation.

 

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The release of cell membrane-derived vesicles is a widespread phenomenon among both prokaryotes and eukaryotes. In gram-negative bacteria, outer membrane vesicles (OMVs) have been shown to play an important role in a range of bacterial physiological processes including protein secretion, intercellular communication and cell envelope stress response. Relatively little, however, is known about these nanoscale structures, how they are formed and what their roles are in relation to bacterial biofilm formation and microbial virulence. By use on a range of advanced molecular biology techniques, we aim at understanding the importance of OMVs in bacterial communities and during bacteria-host interactions. By harnessing this knowledge, it may be possible to develop novel preventive measures for the treatment of chronic bacterial infections.

The core expertise of our research group is in the fields of molecular microbiology, bacterial pathogenesis and intercellular communication (interspecies and cross-kingdom). The main focus of our research is in the study of complex bacterial biofilms and their role in chronic infections and in the development of antimicrobial resistance/tolerance. Our center has access to a number of biofilm model systems, confocal scanning microscopes and animal model systems for studying biofilm infections under both in vitro and in vivo conditions. Through collaborating partners, we also have access to large small molecule libraries and state-of-the-art proteomics analysis equipment. We have ongoing collaborations both within the CBN consortium as well as with both national and international research groups.

 

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Research in the Nanobioorganic Chemistry group focuses on the interface of synthetic (bio-)organic chemistry, biology, and nanobioscience. The starting point in our research is often synthetic peptide chemistry, carbohydrate chemistry, organic chemistry on proteins, or chemistry on nanoparticles or surfaces. The development of new, general chemical tools that enables us to contribute to chemical biology. Solid-phase peptide synthesis plays a central role, both for the fully automated preparation of peptides and in the development of new chemical methods. We are developing new linkers, incl. for the synthesis of peptide thioesters, and are developing the application of microwave heating in peptide synthesis. Also, chemoselective carbohydrate chemistry plays an enabling role.

We aim to study fundamental biological questions in collaboration with dedicated biology groups and to develop new methods for peptide medicinal chemistry. In medicinal chemistry we focus on peptide hormone derived drug candidates for the treatment of metabolic diseases and on protease inhibitors for intervention in cancer. A special focus is on the interaction of peptides with membranes.

 

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The nanoparticle toxicology group consists of ~20 people focussed on adverse health effects related to nanoparticles (NP). We study NP from combustion and engineering for technical application and use in nanomedicine. The research is devoted to NP kinetics and effects especially related to oxidative stress with resulting cell signalling as well as activation and consequences of inflammatory processes. We are renowned for our work in the fields of oxidative stress induced DNA damage and NP-mediated toxicity in vitro and in vivo at molecular and functional level. We also have a record in pharmacology and risk assessment. We are particularly interested in the physical, biological and functional interactions between NP and the cells of the blood and the vascular wall. We have in-house or access to superb molecular toxicology facilities, including transgenic experimental animal facilities, high throughput real-time PCR facility, mass-spectrometry, excellent cell culture facilities, EM, light and fluorescence microscopy, well developed methods for assessing oxidative stress, vascular functions, gene expression patterns, mitochondrial function, apoptosis, membrane expression of adhesion molecules, calcium, nitric oxide and other signalling, protein oxidation and nitration and oxidative modification of bases and strand breaks in DNA at the single cell level. The experimental models address NP target organs, including lungs, vascular system with several functional methods, immune system, liver, gastrointestinal tract and bone marrow with 3-dimensional cocultures and susceptible animals resembling human conditions.

We participate in several European and national projects on NP toxicology. The research work is in collaboration with the main groups in the USA and focused on molecular toxicology in vitro and in vivo of a series of well characterised engineered nanoparticles, including a set from the OECD. The data from these efforts as well as accumulated data on combustion related nanoparticles from our prior research including in vitro, in vivo and human experimental exposure studies, form a large database for comparative risk assessment and understanding mechanisms of NP.

 

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The crucial ability of organisms, or individual cells to sense and react to different external signals (neurotransmitters, hormones, light) is mediated via membrane proteins located at the cell surface. The G protein-coupled receptors (GPCRs) family is by far the largest. Their activation results in interactions with a myriad of proteins in cell involved in complex networks of tightly integrated signal-transduction pathways and responsible of the fine-tuning of the cellular response. Despite of their importance and the numerous physiological consequences of their dysfunction, the signalling pathways of GPCRs are still not fully understood.

A better understanding of the GPCR signalling at the cellular level requires a deeper fundamental elucidation of the protein-protein interactions governing the main GPCRs signalling pathways as well as a deeper understanding of the GPCR structure / function at the molecular level. Most of these information are difficult to elucidate in cells because of the cellular complexity and the difficulty to address each type of protein-protein interaction individually.

We developed several biochemical and biophysical tools to investigate GPCRs in various environments spanning from isolated proteins reconstituted environment to native cells. Our studies exploit fluorescence spectroscopy and microscopies as well as various surface sensitive techniques.

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Research in the Nanobioscience Group focuses on the interface of biophysics, synthetic biology, and nanobiosciences. The chemistry part of the group is represented by Knud J. Jensen Group. The main focus concerns studies of correlation between structure and function. The group have projects on both the solution properties of biomolecules and biomolecular assemblies, and more solid biomolecular systems like gels and melts. A major aim is to make systems that allow detailed structural studies of membrane proteins. This is done using model systems of well defined vesicles where single type of proteins is embedded in the membrane. Another approach is to use nanodiscs, which comprises well-defined 100Å-diameter bilayer membranes allowing only one protein to be enclosed within the limited sized membrane. We aim thereby to study fundamental biological questions with application for medical, pharmaceutics and materials technologies.

Our main experimental techniques are related to structural studies using scattering techniques combined with complex model calculations. We use light, X-ray and neutron scattering as main tools. We use in-house light scattering facilities and SAXS/WAXS instrumentation, and a variety of international large-scale facilities for synchrotron X-ray and neutron scattering. Further in-house facilities include thermal analysis in terms of DSC and ITC.

 

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The optical tweezers group consists of ~15 people, mostly physicists, using various optical techniques such as optical trapping, single particle tracking, and fluorescence microscopy, to study physical properties of biological specimen from the single molecule to whole cell level. As optical traps are the only nanotool capable of reaching inside living organisms while exerting and measuring corresponding values of forces and distances, they hold enormous potential for quantitative studies of biological specimen, even in vivo. The group is among the pioneers of in vivo optical trapping and have developed methods for calibrating forces inside the complex viscoelastic cytoplasm of a living cell. We optically unravel the motility of individual molecules and organelles while keeping the microorganism alive and metabolically competent. Also, we have a sincere interest in achieving a fundamental understanding of the interaction between living cells, their molecular constituents, and nanoparticles. To this end, we perform biophotonical investigations quantifying, e.g., physiological damage and heating associated with optical manipulation of individual nanoparticles and measure relevant interactions. In addition, we use the optical tweezers as a manipulation tool to create and investigate model systems, as, e.g., lipid vesicles and tethers with reconstituted proteins. The group is supported by the University of Copenhagen Excellence program.

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The dynamic but carefully orchestrated organization of small groups of biomolecules (e.g. membrane nano-domains, scaffolding signaling complexes, protein coats) on the nanoscale is essential for many critical cellular processes, however it has proven hard to investigate experimentally and is therefore poorly understood. In this context we are particularly interested on membrane structure and protein-membrane interactions and therefore study a variety of different biological systems with the objective to identify unifying biophysical mechanisms that control on the nanometer scale the structure and function of proteins and membranes. Such mechanisms lead to the emergence of new rules of regulation of biochemical signal transduction networks that transcend classical bi–molecular (e.g. receptor-ligand) interactions.

The problems we are trying to solve are situated at the interface of biology, physics and nanotechnology and to address them experimentally we have assembled a highly inter-disciplinary group that includes molecular biologists, biochemists, physicists, nanotechnologists and material scientists. Our core expertise is advanced biofunctional surfaces that we use to isolate in a controlled environment from single molecules up to reconstituted signaling complexes, and quantitative optical microscopies that we use in combination with a number of other surface sensitive techniques to characterize our samples. Most of our projects are carried out in close collaboration with groups that specialize in protein purification and reconstitution, structural characterization of proteins, molecular dynamics simulations or theory.

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The release of water soluble signaling molecules by fusing membrane bound vesicles with the plasma membrane (exocytosis) has developed as the main means of signaling between cells of multicellular organisms. The most tightly regulated exocytotic process takes place in the synapses of the brain, where neurotransmitters are released by action potentials within a fraction of a millisecond to carry information between cells. The kinetics and plasticity of this process plays decisive roles for the higher functions of the brain, such as learning, memory and processing of sensory information.

We are interested in understanding the mechanism and inner workings of the molecular machinery for exocytosis. At the heart of this process is the SNARE-complex, which bridges the membranes destined to fuse and provides the energy needed for membrane fusion, whereas other proteins such as Munc18-1, synaptotagmins and complexins are required for various regulatory and essential functions, which are poorly understood. Our core expertise is advanced electrophysiological, electrochemical and optical measurements of exocytosis, which are used in combination with knock-out mice and viral overexpression techniques. Mutagenesis is used to perform structure-function analysis of the exocytotic machinery. Most of our projects are carried out in close collaboration with groups specializing in mouse genetics, protein biochemistry, and electron microscopy.

 

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