How does the endocannabinoid system in the zebrafish function at the molecular and phenotypic levels and how is it linked to the stress axis?

To increase clinical success rate of drugs, a better understanding of drug action mechanism and disease dynamics is required. Metabolomics, which studies small molecules involved in biochemical processes in organisms, has shown to be a useful tool for this better understanding.

In this thesis, a system pharmacology approach, integrating metabolomics, pharmacology and chemical biology, was applied to understand and modulate the endocannabinoid system across different model systems (cells, zebrafish, mice and humans).

In this thesis, we have studied the potential of the zebrafish larval model in studying the ECS, as a complementary model to the existing rodent models.

What are the functions of the endocannabinoid system?

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

This thesis describes the use of an activity-based proteomics method to study the endocannabinoid system.

Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central…

The endogenous compound anandamide – often referred to as the body’s own marijuana – plays a role in erasing memories of a traumatic event. This was discovered by an international team led by Leiden chemist Mario van der Stelt. The results have been published in Nature Chemical Biology and may provide…

Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…

This thesis describes the development and optimization of the first molecular tools to study the enzyme PLA2G4E.

The current projects of the Molecular Physiology group focus on proteins of the endocannabinoid system, kinases and antibacterial targets. MSc- and BSc-students can contact Jessica van Krimpen-Kraaijenoord to apply for research internships.

Since its discovery thirty years ago, it remained a mystery: how does the body’s own marijuana move between nerve cells in the brain? Mario van der Stelt and his research group have now uncovered the answer. This insight could aid the development of new treatments for pain and neurological disorders…

PhD defence

PhD defence

Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.

Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process.

Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

The endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an interesting therapeutic target and hard to study.

The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered…

Synthesis and application of chemical biology tools to study immunomodulatory signaling lipids.

Lipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of the individual signaling lipids in inflammatory processes and related conditions in health and disease is…

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids.

Chemical biologists from Leiden, led by Dr Mario van der Stelt, have discovered substances that can reduce inflammation processes in the brain. This is a first step in the development of potential medicines for the treatment of brain diseases like Alzheimer's and Parkinson's. Published in Proceedings…

The predication of the effect (efficiency and toxicity) of a drug in a patient is very important in (i) clinical decision support and (ii) the development of novel drug treatments. We apply our technology and methods to find biomarkers for key disease pathways and toxicity in clinical studies and in…

Supervisor: Andrea Martella

TRANSVAC is a collaborative infrastructure project funded by the European Commission (EC), initially under the 7th Framework Programme (FP7) and currently under Horizon 2020. The project is a joint effort of leading European groups working in the field of vaccine development, and is coordinated by…

Grants awarded to molecular physiology research

PhD candidate Marc Baggelaar of the Leiden Institute of Chemistry (LIC) graduated cum laude on Thursday 6 April. His thesis on the endocannabinoid system in the brain is very comprehensive and of high quality, according to the jury. ‘A very talented young scientist, that definitely belongs to the top…

Leiden chemical biologists led by Dr Mario van der Stelt have developed a method to facilitate the search for new drugs. This method has allowed them to take an important first step in the development of a drug against obesity.

We perform multidisciplinary research at molecular, cellular, and organismal levels of animal biology to increase fundamental understanding of health and disease.

Bringing together institutes and research groups, how do you do that? The Faculty of Science set up a joint research theme and financed three PhD positions. After four years, the profiling programme Endocannabinoids expires. ‘It really brought us together, and the collaborations remain.’

For his ground-breaking chemical biological research, a VICI-grant has been awarded to Mario van der Stelt, professor of Molecular physiology at Leiden University. In a new research line, he aims to discover binding sites for new medicines against inflammations in the brain.

Mario van der Stelt has been appointed Professor of Molecular Physiology at the Leiden Institute of Chemistry with effect from 1 November 2017.

Endocannabinoids - the body's own marijuana - are promising departure points for drug research. Professor of Molecular Physiology Mario van der Stelt examines whether inhibiting their production can be a way to fight inflammatory brain disease and to combat obesity. Inaugural lecture 19 October.

Multiple Sclerosis, Parkinson’s and Alzheimer’s disease are the most common neurodegenerative disorders. Unfortunately, no effective treatments are currently available to halt the progression of these neuroinflammatory diseases [1].

With cancer, a person’s body cells grow uncontrollably. Putting together a detailed picture of how this comes about makes it possible to develop efficient therapies. Researchers at the Leiden University Medical Centre (LUMC) and Leiden University are working together to gain a better understanding…

Hui Deng (MSc.), a PhD-student in the department of Molecular Physiology, has received an award for the best oral presentation during the 26th International Cannabinoid Research Society (ICRS) conference with more than 300 participants in Bukovina, Poland. Hui Deng presented her work on “Rapid and…

Mario van der Stelt (Head of the department of Molecular Physiology at the Leiden Institute of Chemistry) has received the Young Investigator Award from the International Cannabinoid Research Society during the annual meeting of the society in Montreal, Canada. The Young Investigator Award was given…

How do you ensure that a drug has an effect on the right protein – and nothing else? Chemist Anthe Janssen explored various methods for determining the selectivity of potential medicines. He also looked at the substance BIA 10-2474, after a man died in a French clinical trial in 2016. PhD defence on…

There are many complex links in the chain that provides patients with new drugs: from fundamental science, to clinical tests, to production. The entire chain can be found in Leiden. Leiden University, the Leiden University Medical Center (LUMC) and the businesses at the Leiden Bio Science Park (LBSP)…

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