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Entstehung und Funktion von Peptid Endocannabinoiden

English title Origin and functional roles of peptide endocannabinoids
Applicant Gertsch Jürg
Number 163359
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Pharmacology, Pharmacy
Start/End 01.01.2016 - 30.06.2019
Approved amount 549'586.00
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All Disciplines (4)

Discipline
Pharmacology, Pharmacy
Organic Chemistry
Biochemistry
Cellular Biology, Cytology

Keywords (1)

Endocannabinoid System

Lay Summary (German)

Lead
Das Endocannabinoid System ist ein molekulares Netzwerk aus Fettsäure-ähnlichen Stoffen und G-Protein gekoppelten Rezeptoren, welches eine wichtige Rolle im Gehirn und im Immunsystem spielt. In diesem Projekt werden neu entdeckte körpereigene Peptide (sog. Pepcans) untersucht, welche die Cannabinoid-Rezeptoren modulieren.
Lay summary
Das Endocannabinoid-System kontrolliert die Ausschüttung von Neurotransmitter an chemischen Synapsen, wird aber auch in der Peripherie aktiv, wo es entzündliche Prozesse und zellulären Stress reguliert. Die derzeit bekannten Stoffe in diesem System sind die von der Fettsäure Arachidonsäure abgeleiteten Endocannabinoide, welche die Cannabinoid-Rezeptoren aktivieren. In einem SNF geförderten Forschungsprojekt haben wir unlängst neuartige Peptide (Peptid Endocannabinoide oder Pepcans) in Neuronen und in der Nebenniere identifiziert, welche die Aktivität der Endocannabinoide signifikant modulieren können. Wir versuchen nun zu verstehen, wie diese Peptide entstehen und was sie im Körper bewirken. Dazu verwenden wir gesundes und krankes Gewebe, sowie Krankheitsmodelle. Wir wollen die Enzyme identifizieren, welche für die Produktion der Pepcans verantwortlich sind und die beobachteten Effekte (Bindung und Modulation) auf CB1 und CB2 Rezeptoren besser versehen. Dazu werden sowohl modernste biochemische (in vitro), analytische, wie auch genetische Methoden verwendet. Ein besseres Verständnis der Funktion der Pepcans im Körper könnte letztendlich dazu beitragen, neue Medikamente zu entwickeln. Das Projekt soll dazu beitragen, die Grundlagenforschung im Bereich Endocannabinoid-System voranzutreiben, was indirekte und direkte Konsequenzen für eine pharmakologische Intervention im Sinne einer Anwendung in der Medizin haben könnte. Die Erforschung des Endocannabinoid-Systems ist ein Schwerpunkt am IBMM der Universität Bern und hat translationale Implikationen. Sobald man versteht bei welchen Erkrankungen die Rezeptoren eine schützende Funktion ausüben, kann man gezielte Therapien entwickeln.
Direct link to Lay Summary Last update: 29.12.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice
Marino Silvia, de Ridder Daniëlle, Bishop Ryan T., Renema Nathalie, Ponzetti Marco, Sophocleous Antonia, Capulli Mattia, Aljeffery Abdullah, Carrasco Giovana, Gens Marianela Dalghi, Khogeer Asim, Ralston Stuart H., Gertsch Jürg, Lamoureux Francois, Heymann Dominique, Rucci Nadia, Idris Aymen I. (2019), Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice, in EBioMedicine, 44, 452-466.
Scaffold and organism hopping with chemical probes
Gertsch Jürg (2019), Scaffold and organism hopping with chemical probes, in Nature Chemical Biology, 15(5), 428-429.
Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
Granchi Carlotta, Lapillo Margherita, Glasmacher Sandra, Bononi Giulia, Licari Cristina, Poli Giulio, el Boustani Maguie, Caligiuri Isabella, Rizzolio Flavio, Gertsch Jürg, Macchia Marco, Minutolo Filippo, Tuccinardi Tiziano, Chicca Andrea (2019), Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor, in Journal of Medicinal Chemistry, 62(4), 1932-1958.
Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high
Chicca A., Schafroth M. A., Reynoso-Moreno I., Erni R., Petrucci V., Carreira E. M., Gertsch J. (2018), Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high, in Science Advances, 4(10), eaat2166-eaat2166.
β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in miceβ-Caryophyllene is hepatoprotective
Varga Zoltan V., Matyas Csaba, Erdelyi Katalin, Cinar Resat, Nieri Daniela, Chicca Andrea, Nemeth Balazs Tamas, Paloczi Janos, Lajtos Tamas, Corey Lukas, Hasko Gyorgy, Gao Bin, Kunos George, Gertsch Jürg, Pacher Pal (2018), β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in miceβ-Caryophyllene is hepatoprotective, in British Journal of Pharmacology, 175(2), 320-334.
Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage
Petrucci Vanessa, Chicca Andrea, Glasmacher Sandra, Paloczi Janos, Cao Zongxian, Pacher Pal, Gertsch Jürg (2017), Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage, in Scientific Reports, 7(1), 9560-9560.
Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom
Gachet María Salomé, Schubert Alexandra, Calarco Serafina, Boccard Julien, Gertsch Jürg (2017), Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom, in Scientific Reports, 7(1), 41177-41177.
Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor
Bertini Simone, Chicca Andrea, Gado Francesca, Arena Chiara, Nieri Daniela, Digiacomo Maria, Saccomanni Giuseppe, Zhao Pingwei, Abood Mary E., Macchia Marco, Gertsch Jürg, Manera Clementina (2017), Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor, in Bioorganic & Medicinal Chemistry, 25(24), 6427-6434.
Biological evaluation of pyridone alkaloids on the endocannabinoid system
Chicca Andrea, Berg Regina, Jessen Henning J., Marck Nicolas, Schmid Fabian, Burch Patrick, Gertsch Jürg, Gademann Karl (2017), Biological evaluation of pyridone alkaloids on the endocannabinoid system, in Bioorganic & Medicinal Chemistry, 25(22), 6102-6114.
4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice
Patsenker Eleonora, Chicca Andrea, Petrucci Vanessa, Moghadamrad Sheida, de Gottardi Andrea, Hampe Jochen, Gertsch Jürg, Semmo Nasser, Stickel Felix (2017), 4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice, in Journal of Molecular Medicine, 95(10), 1077-1089.
Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
Soethoudt Marjolein, Grether Uwe, Fingerle Jürgen, Grim Travis W., Fezza Filomena, de Petrocellis Luciano, Ullmer Christoph, Rothenhäusler Benno, Perret Camille, van Gils Noortje, Finlay David, MacDonald Christa, Chicca Andrea, Gens Marianela Dalghi, Stuart Jordyn, de Vries Henk, Mastrangelo Nicolina, Xia Lizi, Alachouzos Georgios, Baggelaar Marc P., Martella Andrea, Mock Elliot D., Deng Hui, Heitman Laura H., et al. (2017), Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity, in Nature Communications, 8, 13958-13958.
Editorial: Lung macrophages high on cannabinoids: jamming PAMs and taming TAMs?
Gertsch Jürg (2016), Editorial: Lung macrophages high on cannabinoids: jamming PAMs and taming TAMs?, in Journal of Leukocyte Biology, 99(4), 518-520.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Hanns-Ulrich Zeilhofer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
NIH, Prof. Pal Pacher United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Beat Lutz, University of Mainz Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The 29th Annual International Cannabinoid Research Society Symposium on the Cannabinoids Talk given at a conference BIOCHEMICAL AND ANALYTICAL CHARACTERIZATION OF PEPTIDE ENDOCANNABINOIDS 29.06.2019 Washington, United States of America Spera Irene; Gertsch Jürg; Mandhair Harpreet; Reynoso Ines del Carmen; Glasmacher Sandra;
International Symposium on Bioorganic Chemistry (ISBOC-11) Talk given at a conference Peptide endocannabinoids and their emerging role as CB receptor modulators 27.09.2017 Konstanz, Germany Petrucci Vanessa; Glasmacher Sandra;
Frontiers in MedChem Satellite Meeting, LS2 Talk given at a conference Peptide endocannabinoids and their emerging role as CB receptor modulators 12.02.2017 Bern, Switzerland Gertsch Jürg; Glasmacher Sandra;


Self-organised

Title Date Place
International Endocannabinoid Pharmacology Meeting Bern 25.10.2018 University of Bern, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Swiss Company Makers Talk 17.04.2018 Washington, Switzerland Gertsch Jürg; Bauer Mark Tobias; Glasmacher Sandra;


Associated projects

Number Title Start Funding scheme
141174 Entstehung und Funktion von Peptid Endocannabinoiden 01.05.2012 Project funding (Div. I-III)
141174 Entstehung und Funktion von Peptid Endocannabinoiden 01.05.2012 Project funding (Div. I-III)
189220 Endocannabinoid System Regulation by Sympathoadrenal Axis 01.02.2020 Project funding (Div. I-III)

Abstract

Cannabinoid receptors are G protein-coupled receptors (GPCRs) that are expressed in the CNS (mainly CB1 receptor) and in peripheral tissues, such as immune cells (CB1 and CB2 receptors). They act via Gai/o pathways, depending on the cell type where they are expressed. Both CB1 and CB2 receptors are involved in numerous physiological and pathophysiological conditions and potential drug targets. Modulation of CB1 receptors is implicated in different areas of neurotransmission and inhibition of excitotoxicity, as well as lipid metabolism. Activation of CB2 receptors is a protective mechanism, leading to anti-fibrotic and anti-inflammatory effects in different tissues. CB receptors are activated by arachidonic acid-derived endocannabinoids, such as N-arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG). Recently, a group of endogenous alpha hemoglobin (HBA1/HBA2) derived peptides have been shown to interact with CB1 receptors with high affinity (Kd values in the low nM range) and proposed to be potential endogenous modulators. In the first SNF funded project on the origin and function of peptide endocannabinoids (31003A_141174) we were able generate conclusive receptor pharmacological data on the effects of RVD-hemopressin (here called Pepcan12) on CB1 receptors as a negative allosteric modulator (NAM) (Bauer et al., JBC, 2012) and on CB2 receptors as a positive allosteric modulator (PAM) (yet unpublished). Moreover, we discovered that these peptides are produced exclusively in noradrenergic neurons and in the adrenal medulla (Hofer et al., Neuropharmacology, 2015). Intriguingly, the chromaffin cells of the adrenal medulla exclusively generate Pepcan12 in nmol/mg quantities. In the present project, we will continue our study on the origin and function of this class of peptides (in particular Pepcan12) in the adrenals, with the aim to further elucidate their potential physiological roles mediated via CB receptors in the periphery. Numerous studies have shown that excess activation of CB1 receptors in the periphery can lead to pathophysiological conditions while the widely accepted view is that CB2 activation exerts protective effects. Pepcan12 being a NAM at CB1 receptors and a PAM at CB2 receptors may be a relevant endogenous modulator for the endocannabinoid system (ECS), regulating CB1/CB2 receptor activation under conditions of differential endocannabinoid levels. Given our previous findings we hypothesize that also the sympathetic noradrenergic ganglia produce pepcan12 and that this neuropeptide is released upon stress from the adrenal gland into the blood. Having identified the site of production of these peptides we will now use biochemical tools to elucidate the biosynthesis and degradation of these peptides. Moreover, in collaboration with our in house animal facility and a contract research organization and our collaborator Prof. Beat Lutz (Mainz) we aim to generate mice deficient of the pepcan12 sequence in cells expressing dopamine beta-hydroxylase (DBH) (using DBH Cre mice. Our group will focus on the functional role of peripheral pepcans originating from the adrenal medulla and possible other sources (noradrenergic ganglia and parasympathetic nerves), studying the neuroimmunomodulatory relevance of pepcan12 expression in the presence of endocannabinoids mediated via CB receptors in functional models of endotoxemia and bone homeostasis. In a further subproject, the actual site of action (allosteric binding site) of this peptide at CB1/2 receptors will be identified, as it may be a potential novel target site for small organic molecules. Given our expertise in chemical biology (e.g., Chicca et al., 2014, ACS Chem Biol) we aim to identify small organic molecules that bind to the Pepcan binding site in CB receptors (either blocking or activating) as novel tools to study their physiological relevance.
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