PARTNER 3

Dr. Giovanni Marsicano PhD

U 862 Centre de Recherche INSERM François Magendie; Université Bordeaux 2 "Molecular Mechanisms of Behavioural Adaptation" 146, rue Léo Saignat 33077 Bordeaux, FRANCE

See Group Presentation

ROLE AND CONTRIBUTION

The group of Dr. Marsicano is an expert on the generation of mouse mutant models and in their characterization. He will lead the generation of new mouse models for the study of the role of the cannabinoid system in the development of obesity and the phenotypical characterization of the cannabinoid receptor knockout mice and newly generated mouse mutants in models of diet-induced obesity. The endocannabinoid system is the only one that has yielded a positive antiobesity set of drugs efective in human patients. Newly generated animals will include the generation of conditional mutants for the CB1 receptor (in collaboration with partner 4) and mice bearing the overexpression of enzymes involved in the synthesis and degradation of endogenous cannabinoids. In particular, mice will be generated overexpressing the enzymes monoacylglycerollipase (MAGL) or diacylglycerollipase (DAGL), that are centrally involved in the degradation and synthesis of the endocannabinoid 2-arachidonoylglycerol, respectively. By using conditional targeting and inducible transgenic approaches, the overexpression of these enzymes will be targeted to peripheral tissues, such as adipose tissue or to brain, in order to study the differential effect of an over- or hypo-activated endocannabinoid system at these sites in the development of obesity. Mutant animals will be used on WP2 and WP3 for testing new candidates (for instance drugs able to modulate the synthesis or degradation of endocannabinoids), and specially, WP4 and WP6 for evaluating biomarkers in mutant mice undergoing high fat diet. Behavioural, neuroendocrine and metabolic studies will be performed in the mutant animals an in the ones treated with the new candidates. He will implement additional models (conditional CB1 knockouts, PPARalpha KO mice, etc..) and will assist in the in vivo evaluation of candidates, in association with partners 1, 4, 5 and 6. He will finally participate in the integrative analysis of positive candidates obtained by reprofiling and relevant biomarkers, leading to a proposal of a clinical trial in whole blood biomarkers-phenotyped patients.

SCIENTIFIC PROFILE

The group of Giovanni Marsicano is involved in the generation and phenotypic analysis of mutant mice, with particular interest to the endocannabinoid system. The control of energy balance is one of the predominant functions of this modulatory system and it is at the focus of the scientific interests of the group. In particular, the relative importance of central versus peripheral mechanisms in the role of the endocannabinoid system in the maintenance of proper energy balance is a key question for this group.

CAPACITY TO PROVIDE CONTRIBUTION

The group of Giovanni Marsicano was established at INSERM in Bordeaux (France) in August 2006. Despite the youth, several projects are already running, including the generation of new animal models (see above), the availability of established mouse mutant lines (CB1-KO and 4 different conditional CB1 mutant mouse lines) and the behavioural and autonomic characterization of these mutant lines. In particular, projects are in progress addressing the role of the endocannabinoid system in different aspects of food intake and in the development of diet-induced obesity.

TEAM MEMBERS

Giovanni Marsicano (PhD, male), group leader (general coordination)

Francis Chaouloff (PhD, male), senior scientist (coordination of behavioural experiments on food intake and energy balance)

Pauline Lafenêtre (PhD, female), post-doc

Isabel Matias (PhD, female), post-doc

Astrid Cannich (PhD, female), part-time post-doc

Joana Lourenço, female, PhD student

Luigi Bellocchio, male, PhD student

Delphine Gonzales, female, technician

Klodjan Stafa, master student

RECENT RELEVANT PAPERS

1. Pagotto U, Marsicano G, Cota D, Lutz B and Pasquali R. (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews 27(1):73-100

2. Agarwal N, Amaya F, Pacher P, Constantin C, Brenner GJ, Michalski CW, Tegeder I, Marsicano G, Marian C, Batkai S, Fischer MJ, Reeh P, Kunos G, Lutz B, Kress M, Woolf CJ, Kuner R (2007). Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nature Neuroscience. Jun 10; [Epub ahead of print]

3. Marsicano G*, Goodenough S*, Monory K*, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Ortega Gutiérrez S, van der Stelt M, López-Rodríguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C and Lutz B (2003). CB1 Cannabinoid Receptors and On-demand Defense Against Excitotoxicity. Science 302:84-88.

4. Marsicano G*, Cota D*, Tschöp M, Grübler Y, Schubert M, Auer D, Thöne-Reinecke C, Ortmann S, Flachskamm C, Cervino C, Linthorst A, Pasquali R, Lutz B, Stalla GK and Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112(3):423-31. *, equal contribution

5. Marsicano G*, Wotjak C*, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang, J, Hofmann C, Zieglgänsberger W, Di Marzo V and Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530-34.