Structure and function studies of 7TM G protein coupled receptors as described above using especially metabolic 7TM receptors as model systems (Ghrelin receptor, GPR39, GPR119, TGR5, GPR41/43, GPR40, GPR120, the GIP R etc.) are closely integrated with computational chemistry (Thomas Frimurer at CPR & CMBR, SUND), with medicinal chemistry (Annette Beck-Sickinger, Leipzig University, Trond Ulven, Syddansk University, and Rob Jones Arena Pharmaceuticals, San Diego), with cell biology (Nick Holliday, University of Nottingham, UK) and are currently also being integrated with biophysics based on AMBER mutation suppression technology for incorporation of unnatural amino acids in eukaryotic cell lines (Tom Sakmar, Rockefeller University and B. Holst Lab, INF, KU).
Structure and function of adhesion 7TM receptors (for example GPR56, 64, 112 and 116) is a major new focus area which also includes basic protein chemistry related to expression of receptor domains for use as pharmacological tools, for structural characterization and identification of binding partners (with Matts Wikstrøm CPR, KU).
Site directed “drug discovery”
That is, a package of technologies to exploit knowledge about 7TM receptor structure and function to discover and design novel ligands, i.e. pharmacological tool compounds and drug lead compounds through probing of iterative series of 32 Annual Report 2012 target-customized mini-libraries of small molecule compounds selected by means of computational chemistry (with Thomas Frimurer at CPR, SUND); testing of small molecule and peptide ligands in the in vitro, ex vivo and in vivo setting through various drug delivery systems (with B. Holst Lab, INF, SUND).
Characterization of the in vitro and in vivo functional consequences of genetic variants of especially 7TM receptors and associated proteins especially involved in metabolism (with Oluf B. Pedersen and Torben Hansen, CBMR, SUND, KU & Sadaf Farooqi, Univ Cambridge, UK).
Characterization of the molecular pharmacology (e.g. 7TM receptor, chemo-sensor and adhesion 7TM repertoire as well as adaptor protein and signalling protein repertoire) and cell biology (e.g. functional interplay of receptors and associated proteins in signaltransductosomes and the control of the cellular development and differentiation of enteroendocrine cells from crypt stem cells, miRNA expression and function) of enteroendocrine cells and their interplay with and control of neighbouring enterocytes and nerves – being part of the gut-brain axis.
A major focus is on establishing and exploiting reporter mice expressing, for example variants of GFP/RFP under the expressional control of “promoters” for a) gut hormones, b) grains (secretory granule proteins) and c) potential 7TM chemosensors combined with immunohistochemistry, FACS purification, LC-MS proteomic analysis (with Jesper V.Olsen, CPR, SUND, KU) and for example epigenetic analysis (with Nils Tommerup, IMMI, SUND, KU).
These analytical studies are deeply integrated with an array of functional studies in various ex vivo and in vivo models using, for example novel transgenic animal models and pharmacological tool compounds (with JJ Holst Lab B BMI/CBM and B.Holst Lab and Rodent Metabolic Phenotyping Centre, CBMR, SUND).
The lab has a number of national and international collaborations including – through CBMR – International research Alliances with South Western Medical School (Jeff Zigman Lab) and Gothenburg University, Wallenberg Laboratories (Fredrik Bäckhed Lab) and collaborations with biotech and pharmaceutical industries including with Merck Research Laboratories (Rahway, New Jersey) and Arena Pharmaceuticals (San Diego, CA).