Molecular Pharmacology Laboratory
The common research theme of the Molecular Pharmacology Laboratory is the relationship between structure and function of 7TM (seven transmembrane segment), G protein-coupled receptors.
Structure-function studies of 7TM G protein coupled receptors within in particular the immune system (cytokine and lipid receptors) and the endocrine system (incretin, neuropeptide, melanocortin, melatonin, lipid and orphan receptors). This includes the molecular basis for ligand recognition and receptor activation, action of allosteric and orthosteric agonists, antagonists, super- and inverse agonists. Identification of novel compounds by site-directed drug discovery methods and chemogenomics. Description of signalling phenomena such as constitutive activity, functional selectivity (biased activity) and receptor cross-talk.
The molecular pharmacology is closely integrated with computational chemistry (Thomas Frimurer at CBMC, SUND, David Gloriam at Department of Drug Design and Pharmacology, SUND, and Jon Våbenø at Tromsø University) with medicinal chemistry (Harald Severin Hansen at Department of Drug Design and Pharmacology, SUND, Trond Ulven at University of Southern Denmark, SDU and Bengt Erik at Bergen University University) with nanotechnology for probing receptor-ligand interaction (in collaboration with Gertrud Hjortø, Department of Micro- and Nanotechnology, DTU) with cell biology and virology (Nikolaj Kulahin at Novo, Denmark, Sten Seier Poulsen at BMI, SUND, Thomas N. Kledal, National Veterinary Virology Institute, DTU, Anette Mankerts and Annual Report 2012 31 Bernhard Ehlers, both at Robert Koch Institute, Berlin, and Andreas Sailer at Novartis, Switzerland) and are currently being integrated with various virus-expression systems and development of virus-model systems for the in vivo studies, in particular with respect to in vivo and in situ signalling properties, of wild type and mutated 7TM receptors (see below).
In vivo Metabolic Receptology
We are mainly focusing on incretin hormones (GIP, GLP1), GLP2, neuropeptides (NPY, PYY a.o.), lipid receptors (GPR119 a.o.) as well as orphan receptors of putative impact for metabolic control (GPR26 a.o.), and use in vivo human tests, and rodent in- and ex vivo experiments. The testing in healthy humans, obese and type 1/2 diabetes mellitus takes place in collaboration with Filip Knop and Tina Vilsbøll, Department of Internal Medicine (Diabetologisk Forskningsenhed), Gentofte Hospital, and with the Jens Juul Holst laboratory, BMI, SUND. The rodent test systems are designed and conducted in collaboration with the Jens Juul Holst laboratory, BMI, SUND. The in vivo studies also include test of novel tool compounds in human and rodents.
In vivo Immune Receptology
We are in particular interested in understanding every pharmacology-related aspect of the virus-exploited 7TM receptors. These includes the virus-induced 7TM receptors, such the chemokine receptor EBI1 (or CCR7) and the oxysterol receptor EBI2 (or GPR183), and the virus-encoded 7TM receptors, such as the ORF74-family encoded by rhadinviruses, the BILF1-family encoded by lymphocryptoviruses, and the US28, US27, UL33 and UL78 encoded by human cytomegalovirus (and rodent homologs in the case of UL33 and UL78). The in vivo tests related to EBI2 involves cell-type specific overexpression of human EBI2 in mice, EBI2 knock out models combined with strategies for T-cell depletion (in collaboration with Peter J. Holst, Department of International Health, Immunology and Microbiology, SUND, Allan Randrup and Jan Pravsgaard Christensen, Lab. For Experimental Virology, SUND). Furthermore, we are establishing various forms of transgenic animal models for the virus-encoded receptors (for example with Helen Farrell and Nick Davis Poynter, Queensland University) and for virus-encoded ligands for endogenous receptors (Anette Mankertz, Robert Kock Institute, Berlin), in addition to testing in vivo novel pharmacological tool compounds (in collaboration with Andreas Sailer, Novartis, Switzerland and Rob Jepras, GSK, Stevenage, London) and to determine the immune-regulating and virus-implicated functions of 7TM receptors. An important part of the in vivo rodent studies is to integrate and probe knowledge from basic molecular pharmacology (see above) with in vivo immunology, virology and pharmacology. For example probing the immunological, in vivo importance of the constitutive receptor activities (a common phenotypic trait of many virus-exploited 7TM receptors) by novel inverse agonists/ antagonists and transgenic models using adeno- and retrovirus models.
Part of the research theme
Mette M. Rosenkilde