Endocannabinoids (eCB) are novel class of endogenous lipid molecules that has fundamental roles in the regulation of various biological activities. In the brain, eCB molecules – anandamide and 2-arachidonoylglycerol (2-AG) – are produced upon demand and activate type-1 cannabinoid (CB1) receptors to exert its effects: the modulation of various long- and short-term changes in synaptic efficiency related to emotion, pain, appetite and memory. Abnormal eCB signaling is associated with several pathological conditions such as inflammation, drug addiction and neurodegenerative disorders, indicating a therapeutic potential of targeting this system. Therefore, elucidating the detailed mechanism underlying the regulation of eCBs in both normal as well as diseased conditions are important subjects for future studies.
My long-term research goal is i) to define the molecular mechanism underlying the physiological regulation of endocannabinoids and other bioactive lipids, and ii) to determine their relevance to the pathogenesis of certain neurological diseases.
I. Defining the role of eCB in the pathogenesis of Alzheimer’s disease The objective of the research is to examine whether changes in eCB signaling contribute to cognitive dysfunction in AD. Based on our results obtained from lipidomic analyses of postmortem human brains, I hypothesize that deficits in eCB signaling contribute to Aβ-induced synaptic pathogenesis, which underlie the cognitive dysfunction of AD patients.
II. eCB dysregulation in Fragile X mental retardation syndrome (FRAX) FRAX is the most commonly inherited form of mental retardation and the most common genetic cause of autism. The high occurrence of autism spectrum disorders (ASD) in FRAX, along with the fact that this disease is caused by a well-defined genetic problem, make it a unique model system for the study of autism, the genetics of which is highly complex. In our previous studies, we found that fmr1-/- mice, an animal model for FRAX, display a significant impairment in mGlu5 receptor-dependent plasticity mediated by 2-AG and CB1 receptors at excitatory synapses of the brain. Importantly, this deficit is associated with the spatial and functional uncoupling of the mGlu5 receptor signalosome. I hypothesize that dysregulation of FMRP-dependent DGL-α activation may cause abnormal eCB signaling, which contribute to FRAX pathology. Therefore, I will i) define the molecular pathophysiology of eCB disruption in fmr1-/- mice; and ii) test whether pharmacological or genetic restoration of eCB signals alleviate the molecular and behavioral pathology of fmr1-/- mice.
III. Defining the unidentified molecular components of eCB synthesis and metabolism Although many of the proteins importantly involved in the biosynthesis, inactivation and modulation of eCBs have been characterized and their genes cloned, some of the key players still await to be molecularly identified, including the N-acyl transferase (NAT) and 2-AG transporter. I will use modern biochemical and molecular biological methods to purify, clone and characterize the proteins.