Project Details
Projekt
Role of peripheral endocannabinoid system in atherosclerosis
Subject Area
Cardiology, Angiology
Term
from 2014 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262061163
Despite major advances in cardiovascular research, atherosclerosis remains a major health burden and is responsible for the majority of all deaths worldwide. An endogenous lipid signaling system, the so-called endocannabinoid system has recently evolved as an important regulator in both physiological and pathophysiological processes. This system comprises at least two distinct membrane receptors, CB1 and CB2, their endogenous ligands (named endocannabinoids) as well as enzymes for ligand biosynthesis and inactivation. We and others have shown increased activity of the endocannabinoid system in atherosclerosis and its related cardiovascular risk factors, obesity, dyslipidemia, diabetes and endothelial dysfunction. However, the causal role of the elevated endocannabinoid tone and proposed opposing role of CB1 and CB2 receptors in atherosclerosis is not well understood. Simple genetic approaches based on global receptor deficiency are hampered by the fact that both receptors are widely expressed within the central nervous system as well as most peripheral organs, including the cardiovascular system. Thus, it is difficult to dissect the specific contribution of vascular and immune cell CB1 and CB2 signaling. Secific aims: (1) To clarify the specific role of vascular and hematopoietic cannabinoid receptors in the pathogenesis of atherosclerosis based on bone marrow chimeras and cell-specific mutation. (2) To investigate the specific contribution of elevated endocannabinoid 2-AG tone and endocannabinoid-related fatty acid amides in the pathogenesis of atherosclerosis (3) To shed light on the intracellular signaling pathways underlying the opposing pathophysiological effects of the two cannabinoid receptors. Based on this multi-disciplinary approach which combines cardiovascular biology, immunology and receptor biochemistry, we hope to gain a detailed view of the complex immunomodulatory and cardiometabolic effects of endocannabinoids that are key determinants of atherosclerosis. This should help advancing our current understanding of the pathology and potentially lead to more efficient and specific therapies and better cardiovascular risk assessment.
DFG Programme
Research Grants
