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Endocannabinoid System Regulation by Sympathoadrenal Axis

English title Endocannabinoid System Regulation by Sympathoadrenal Axis
Applicant Gertsch Jürg
Number 189220
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 01.02.2020 - 31.01.2024
Approved amount 700'000.00
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All Disciplines (4)

Discipline
Pharmacology, Pharmacy
Cellular Biology, Cytology
Organic Chemistry
Biochemistry

Keywords (9)

Receptor Pharmacology; Neuroimmunomodulation; Neuropeptides; Cannabinoid Receptors; Inflammation; Sympathetic nervious system; Novel neuropeptides; Endocannabinoid System; Noradrenergic neurons

Lay Summary (German)

Lead
Das Endocannabinod-System vermittelt Lipidsignale in einem Stresskontext über die Cannabinoid Rezeptoren CB2 und CB2. Es reguliert die Signalübertragung in chemischen Synapsen und moduliert entzündliche Prozesse. Kürzlich wurden Peptide gefunden, die diese Rezeptoren unterschiedlich regulieren können. Interessanterweise sind diese Peptide in den Nebennieren und dem Sympathikus exprimiert. In diesem Projekt untersuchen wir die Rolle dieser Peptide in verschiedenen Krankheitsmodellen wo das Endocannabinoid-Sytem reguliert ist.
Lay summary

Mittels genetischer Methoden werden die Peptide in Mäusen spezifisch in der Sympathikus-Nebennierenachse durch gezielte Mutationen inaktiviert. Ferner soll das Gen das für die Produktion dieser Peptide vollständig untersucht werden. Die Rolle dieser Peptide wird in Modellen für Neuroinflammation, Stress und metabolischem Stress untersucht werden. Mittels modernster analytischer Methoden wird die Produktion dieser Peptide in den Geweben quantifiziert werden. Die Rolle der Peptide Endocannabinoide (Pepcans) für die Funktion des Endocannabinoid-Systems soll erstmals in vivo untersucht werden. Basierend auf existierenden Daten von Mäusen, wird Blut und Liquor von MS Patienten auf die Veränderung dieser Peptidmuster untersucht. Spezifisch sind wir daran interessiert, die Veränderung der Peptide und Endocannabinoide als potentielle Biomarker zu verstehen.

Direct link to Lay Summary Last update: 23.12.2019

Responsible applicant and co-applicants

Employees

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Natural persons


Name Institute

Associated projects

Number Title Start Funding scheme
198127 High-resolution Electron Impact Ionization Mass Spectrometer equipped with a Gas Chromatograph 01.01.2021 R'EQUIP
163359 Entstehung und Funktion von Peptid Endocannabinoiden 01.01.2016 Project funding (Div. I-III)

Abstract

The endocannabinoid system (ECS) is an important signaling network comprising the primary endocannabinoids (eCBs) 2-AG and AEA, lipids that activate the G protein-coupled cannabinoid receptors CB1 and CB2, GPR55, as well as different ion channels and intracellular receptors. The ECS is a protective and pro-homeostatic system that reacts to intracellular calcium activation from a variety of receptors (i.e., stress signals). The ECS can have different roles in different tissues and cells. In the CNS it typically mediates a retrograde inhibition at chemical synapses with subsequent inhibition of neurotransmitter release. In the periphery, CB receptors differentially modulate immune and metabolic processes in which CB1 receptor over-activation can be detrimental [8]. On the contrary, CB2 receptor activation inhibits inflammatory and fibrotic processes. Given the non-selectivity of endocannabinoids (eCBs) at CB1/2 receptors and the paradoxical co-occurrence of CB1/CB2 on immune cells, it is postulated that CB receptors could be modulated differentially, e.g. by allosteric mechanisms. Recently, others and we have reported the potential allosteric actions of peptide endocannabinoids (pepcan-12, RVD-hemopressin) specifically at CB1 (negative) and CB2 (positive) receptors in vitro. However, the physiological role of pepcan-12 remains unclear. In vivo, pepcans are expressed exclusively in the premotor autonomic nucleus in the brain (locus coeruleus, A2, A5 and A7 nuclei), adrenal medulla and possibly sympathetic nerve termini, i.e. noradrenergic cells. This strongly suggests a tangible interaction between the sympathoadrenal system and the ECS. In vivo, it is unknown whether eCBs/pepcans communicate as chemical signals across tissues and if pepcans play a role as allosteric modulators at CB receptors. The best way to address this question is by gene-targeting in mice. This project is a continuation of the previous grant 31003A_163359 in which an inducible Cre-activated knock-in vector; ES transfection and heterologous recombination have already been successfully achieved. Employing a conditional polypoint mutant pepcan-12 mouse-line using Flp and Cre-activated technology in combination with targeted ECS and endocannabinome analyses of the mouse adrenal glands, in this project we will challenge the hypothesis that pepcans are involved in ECS regulation. We will investigate the involvement of the adrenal glands as ECS modulator releasing pepcans/eCBs via the sympathetic nervous system (SNS) to different organs. AIM 1: We will cross chimeras to generate a C57BL/6 Pepcan polypoint mutant knock-in mouse-strain bearing a tamoxifen-dependent Cre recombinase expressed under the control of the dopamine-ß-hydroxylase (DBH). Because the LC is implicated in arousal, response to novelty, and cognitive functions, including decision-making and behavioral flexibility, the conditional pepcan mutant strain will be analyzed in basic behavioral paradigms. To explore the role of pepcan-12 in acute and chronic inflammation, we will employ mouse models of endotoxemia and experimental autoimmune encephalomyelitis (EAE) model in collaboration with Prof. Britta Engelhardt, (Universtiy of Bern). We aim to test the hypothesis that pepcans modulate central locus coeruleus activation network connectivity and metabolic processes via CB1 and CB2 modulation peripherally. AIM 2: To understand whether adrenals are involved in the eCB tone in the periphery, regulation of ECS enzymes (serine hydrolases) and the endocannabinome in adrenals will be characterized in the animal experiments mentioned above biochemically profiling these glands. Using adrenalectomized and control mice, we will profile short- and long-term biochemical changes induced in the ECS in different organs, including blood and brain under normal, inflammatory and stress conditions. Combining targeted metabolomics (LC-MS/MS) with functional proteomics and phenotypic analyses we will challenge the hypothesis that eCBs and/or pepcans exert not only auto/paracrine but also endocrine effects via the sympathoadrenal axis. AIM 3: In light of preliminary data from the EAE model, pepcans could be regulated in neuroinflammation and serve as novel biomarkers. In collaboration with Prof. Andrew Chan and the Biobank (BBS) Inselspital Bern, human serum and CSF of patients with different levels of neuroinflammation and severity of multiple sclerosis will be analyzed (3a). Overall, being potential CB1 receptor negative and CB2 positive allosteric physiological modulators, pepcans are bona fide endogenous ECS modulators that might shift the CB1/CB2 activation ratio in peripheral organs through sympathetic mechanisms. A role of adrenals in the eCB tone in the periphery may potentially link stress to the ECS in peripheral organs. The project explores a hitherto poorly understood and potentially critical modulation of the ECS with major implications for the action of eCBs/cannabinoids in pathophysiological processes.
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