Endocannabinoids are lipid messengers that modulate various physiological functions by activating the cannabinoid CB1 and CB2 receptors. While the metabolism of endocannabinoids and their action at the CB receptors is fairly well studied, the molecular mechanisms governing their release and transport…

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?

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

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

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…

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 investigated miniaturized mass spectrometry (MS)-based analytical methods to address challenges in analyzing biomass-restricted biological samples.

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.

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

Neurodegenerative diseases pose a large medical and societal challenge. The etiology of these diseases is still poorly understood, which makes drug discovery for these diseases difficult.

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.

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.

Microglia support the central and peripheral nervous system by forming the first line of defense against hazardous events. Microglia are increasingly acknowledged as critical players in neurodegenerative diseases, highlighting them as potential therapeutic targets.

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

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…

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…

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.

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.

Synthesis and application of chemical biology tools to study immunomodulatory signaling 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…

Supervisor: Andrea Martella

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.

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.’

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…

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)…