PARTNER 4

Dr. Beat Lutz PhD Professor of Physiological Chemistry

Institute of Physiological Chemistry and Pathobiochemistry Johannes Gutenberg-University Mainz Duesbergweg 6 D-55099 Mainz GERMANY

See Group Presentation

ROLE AND CONTRIBUTION

Dr. Beat Lutz will lead WP2, organizing in vivo testing of the efficacy of candidates obtained by reprofiling, in animal models of obesity or metabolic dysfunction. These models will include different lines of cannabinoid CB1 receptor-deficient mice which he has generated, and additional models of transgenic mice affecting visceral sensory system and mediators involved in the regulation of feeding and metabolism. Partners 1, 3, 5 and 6 will assist him on this work. He will assist Partner 6 in the investigation of the mechanism of action of the new candidates (WP3). He will also provide samples from the genetically modified animals developed in his laboratory, for obtaining whole blood and adipocyte biomarkers associated with obese/lean phenotypes. Finally, he will assist the consortium on the integration of both reprofiling and research on biomarkers, in order to propose candidate for clinical trials in well phenotyped patients. The work will be done by his team and the scientific personnel contracted under this grant.

SCIENTIFIC PROFILE

Dr. Lutz is full professor for Physiological Chemistry at the Johannes Gutenberg-University in Mainz, Germany. After studying Biochemistry at the Swiss Federal Institute of Technology in Zurich, Switzerland, he worked as postdoctoral researcher at Harvard Medical School, Boston, at Baylor College of Medicine, Houston, and at the German Cancer Research Center, Heidelberg. In 1997, he was appointed as Independent Junior Researcher at the Max-Planck-Institute of Psychiatry in Munich, at an assistant professor level. He obtained the Organon Prize for Biological Psychiatry for his research on cannabinoid receptors, a stipend from the Hertie Foundation in the Neuroscience Excellence program, and a research grant from the European Association of the Study of Diabetes (EASD). He published more than 60 peer-reviewed papers in the recent few years, in particular in the field of basic research on endocannabinoids, including the roles in feeding behaviour and stress axis regulation. His current research concerns several investigations regarding the roles of the endocannabinoid system in feeding and energy metabolism, both in central as well as in peripheral tissues, such as adipocytes and sympathetic neurons.

CAPACITY TO PROVIDE CONTRIBUTION

The Department of Physiological Chemistry provide excellent facilities for a broad phenotypic analysis of mice that are genetically or pharmacologically manipulated. Several animal caretakers and technicians are available for large scale investigations, handling of animals and genotyping of mutant mice. Fully equipped molecular biology and cell culture laboratories are present. Behavioural equipments for a large variety of assays are also available. Sufficient animal housing is present. In addition, by the end of 2008, another SPF animal house will be available next to the institute.

TEAM MEMBERS

Present group members:

Beat Lutz, Prof., Ph.D., male; supervision of entire program, coordination and interaction with other groups.

Krisztina Monory, Ph.D., female; group leader position in the Institute, management of genetic and pharmacological experiments

Giacomo Mancini, Ph.D. student, male; pre-doctoral student currently analyzing the roles of CB1 receptors in energy metabolism using mouse mutants with adipocyte-specific deletion of CB1 receptors.

Andrea Conrad, technician, female; experimental support for a large variety of experiments in mice, including blood sampling, glucose tolerance test, and ELISA.

RECENT RELEVANT PAPERS

Monory M, Blaudzun H, Massa F, Kaiser N, Lemberger T, Schütz G, Wotjak CT, Marsicano G*, Lutz B*. Genetic dissection of behavioural and autonomic effects of Δ9-tetrahydrocannabinol in mice, PLoS Biol, in press. (*, equal contributions)

Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM, Monory K, Marsicano G, Matteoli M, Canty A, Irving AJ, Katona I, Yanagawa Y, Rakic P, Lutz B, Mackie K, Harkany T. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science. 2007 May 25;316(5828):1212-6.

Marsch R, Foeller E, Rammes G, Bunck M, Kossl M, Holsboer F, Zieglgänsberger W, Landgraf R, Lutz B, Wotjak CT. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci. 2007 Jan 24;27(4):832-9.

Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grubler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U. Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology. 2007 Apr;148(4):1574-81.

Massa F, Sibaev A, Marsicano G, Blaudzun H, Storr M, Lutz B. Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis. J Mol Med. 2006 Feb;84(2):142-6.

Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wolfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 2006;51:455-66.

Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113(8):1202-9.

Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Thöne-Reinecke C, Ortmann S, Cervino C, Linthorst A, Pasquali R, Lutz B, Stalla GK, Pagotto U. Decreased fat mass in mice deficient for cannabinoid receptor 1 is due to decreased orexigenic drive and impaired adipocyte differentiation. J Clin Invest. 2003;112:423-431.

Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Grazia Cascio M, Ortega Gutiérrez S, van der Stelt M, Luz López-Rodriguez M, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B. CB1 cannabinoid receptors mediate on-demand defense against excitotoxicity. Science. 2003;302:84-88