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Inactivation of peripheral cannabinoid receptor 1 (CB1R): a promising therapeutic strategy to improve metabolic disorders linked to obesity
France (ANEMF) - UFR Sciences de santé Dijon, Dijon
UMR1231 INSERM-University of Burgundy « Lipids, Nutrition, Cancer » Team Pathophysiology of Dyslipidemia (PADYS) Faculté des Sciences Gabriel 6, Bd Gabriel 21000 Dijon
Type of Research Project
- Basic science
What is the background of the project?
It is now well established that obesity is associated with an overactivation of endocannabinoid system (ECS). The ECS is defined as a set of receptors able to bind endogenous ligands (endocannabinoids), synthesized and degraded by specific enzymes. This system includes two main membrane receptors, the cannabinoid receptors 1 and 2 (CB1R and CB2R), and two main endogenous agonists, N-arachidonoyl-ethanolamine (anandamide or AEA) and 2-arachidonoyl-glycerol (2-AG). Evidence has accumulated from studies using the global CB1R antagonist Rimonabant and CB1R-deficient (CB1R-/-) mice that these receptors are key contributors to the development of metabolic deregulations associated with obesity. While global CB1R blockade showed promise in improving many cardio-metabolic parameters in obese and overweight patients, the pharmaceutical development of this class of compounds has been halted because of adverse neuropsychiatric side effects. Nevertheless, many studies have highlighted a role for peripheral CB1R in the regulation of obesity and its metabolic sequelae. Indeed, while CB1R is localized predominantly in the brain, this receptor has also been described as an important regulator of energy homeostasis in a number of peripheral. It is suggested that endocannabinoid levels of these tissues are increased during obesity.
What is the aim of the project?
The main objective of this project is to evaluate the capacity of some 2nd generation CB1R antagonists (with an action restricted to the periphery) to improve metabolic disorders linked to obesity and gain a better understanding of their mechanism of action using diet-induced obese mice and in vitro models.
What techniques and methods are used?
C57BL6/J mice will be challenged with a high fat diet for 15 months and then treated either with a placebo or a peripherally-restricted CB1R antagonists synthesized and developed in-house or in collaboration with Dr. George Kunos, NIH, USA or commercially available in order to assess the efficacy of these compounds to block CB1R and improve metabolic parameters. For that, metabolic studies will be performed such as glucose and pyruvate tolerance tests and insulin sensitivity test. Blood and tissues (liver, adipose tissues, muscle) will be collected at the end of the treatment to analyze plasma parameters and evaluate expression of genes and proteins involved in carbohydrate and lipid metabolism.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- If the project includes “lab work”
- the student will take active part in the practical aspect of the project
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will have to: - Study recent bibliography related to the research area consulting databases of references such as PubMed. - take active part to animal treatment and tissue collection with the help of a supervisor - perform cell culture experiments - measure biochemical plasma parameters such as glucose, insulin, incretins, lipids, lipoproteins, glycerol, cytokines, adipokines…using biochemical assays and ELISA kits (enzyme-linked immunosorbent assay kits). - perform protein extractions and western blots - perform nucleic acid extraction and RT-PCR (Reverse transcription polymerase chain reaction) - analyse results - perform statistical tests - take active part to the discussion during lab meetings
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The student will be trained to respect the proper laboratory safety rules (2h meeting with an engineer) and good laboratory practices for cell culture (2h meeting with a researcher and taking part to experimentation)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
A previous experiment in basic or pre-clinical research in a laboratory is required
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- Piazza PV; Cota D; Marsicano G. Neuron. 2017. The CB1 Receptor as the Cornerstone of Exostasis. Mar 2; 93(6):1252-1274. Review.
- Tam J; Hinden L; Drori A; Udi S; Azar S; Baraghithy S. Eur J Intern Med. 2018. The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system. Mar; 49:23-29. Review.
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