Utilization of The Endocannabinoid System as a Novel Therapeutic Target for Anxiety and Related Disorders
Mentor 1
Elizabeth Liedhegner
Start Date
28-4-2023 12:00 AM
Description
Nearly one in five Americans have suffered from an anxiety disorder within the last year with as many as 33% experiencing anxiety within their lifetime. Anxiety disorders including generalized and social anxiety, phobias, and post-traumatic stress disorder (PTSD) are currently treated with several types of medications such as selective serotonin reuptake inhibitors. However, many patients still exhibit unmanageable symptoms. Thus, there is a great need for novel therapeutic strategies to help this patient population. One such target lies within the endocannabinoid system (ECS) which is involved in fear and anxiety management. Indeed, decreased ECS tone has been associated with anxiety and anxiety-like disorders. The ECS is a lipid signaling system that is widely expressed throughout the body consisting of two expressed G-protein coupled receptors, namely cannabinoid receptor 1 and 2 (CB1 and CB2, respectively), and their lipid agonists, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). AEA and 2-AG, are thought to be synthesized on-demand and released into the synaptic cleft to modulate neuro-signaling in a retrograde manner. Due to the lipophilic nature of AEA and 2-AG, it’s likely that carrier molecule(s), such as sterol carrier protein-2 (SCP-2), facilitates lipid ligand movement. SCP-2 is an intracellular protein that transports a variety of lipids, such as cholesterol and fatty acids. Additionally, SCP-2 has been shown to traffic AEA in vitro. Inhibition or knock-out of SCP-2 in a mouse model is anxiolytic. Taken together, our overarching hypothesis is that inhibition of SCP-2 will increase the cellular concentration endocannabinoids resulting in reduced anxiety. This project aims to identify potential inhibitors of SCP-2 from a commercially available small molecule library. We will utilize a fluorescent competitive binding assay to monitor release of NBD-stearate from SCP-2. Once we have identified promising inhibitors from the screening assay, we will measure Ki and EC50s to inform cellular uptake studies.
Utilization of The Endocannabinoid System as a Novel Therapeutic Target for Anxiety and Related Disorders
Nearly one in five Americans have suffered from an anxiety disorder within the last year with as many as 33% experiencing anxiety within their lifetime. Anxiety disorders including generalized and social anxiety, phobias, and post-traumatic stress disorder (PTSD) are currently treated with several types of medications such as selective serotonin reuptake inhibitors. However, many patients still exhibit unmanageable symptoms. Thus, there is a great need for novel therapeutic strategies to help this patient population. One such target lies within the endocannabinoid system (ECS) which is involved in fear and anxiety management. Indeed, decreased ECS tone has been associated with anxiety and anxiety-like disorders. The ECS is a lipid signaling system that is widely expressed throughout the body consisting of two expressed G-protein coupled receptors, namely cannabinoid receptor 1 and 2 (CB1 and CB2, respectively), and their lipid agonists, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). AEA and 2-AG, are thought to be synthesized on-demand and released into the synaptic cleft to modulate neuro-signaling in a retrograde manner. Due to the lipophilic nature of AEA and 2-AG, it’s likely that carrier molecule(s), such as sterol carrier protein-2 (SCP-2), facilitates lipid ligand movement. SCP-2 is an intracellular protein that transports a variety of lipids, such as cholesterol and fatty acids. Additionally, SCP-2 has been shown to traffic AEA in vitro. Inhibition or knock-out of SCP-2 in a mouse model is anxiolytic. Taken together, our overarching hypothesis is that inhibition of SCP-2 will increase the cellular concentration endocannabinoids resulting in reduced anxiety. This project aims to identify potential inhibitors of SCP-2 from a commercially available small molecule library. We will utilize a fluorescent competitive binding assay to monitor release of NBD-stearate from SCP-2. Once we have identified promising inhibitors from the screening assay, we will measure Ki and EC50s to inform cellular uptake studies.
