Academic History
BS, Massachusetts Institute of Technology, 1953
PhD, Wayne State University, 1959
Postdoctoral Training
Fellow, Weizmann Institute, 1960
Fellow, Brandeis University, 1961
Lipid Mediated Signaling Pathways
My current research interest is in the area of bioactive lipid-mediated signaling pathways. N-arachidonoyl glycine (NAGly), an endogenous lipoamino acid, with potential physiological and pharmacological significance, is found at high levels in rat brain, spinal cord and other sites throughout the body. It is the simplest member of a subfamily of the super family of eicosanoids, and comprises more than 50 members. Prior reports had shown that NAGly acts to elicit analgesic properties similar to those reported for the closely related endocannabinoid anandamide. It is a putative ligand for GPR18, a GPCR expressed in spleen, testis and brain where it plays a role in induced cellular migration of cells to sites of damage. Unlike anandamide, NAGly does not bind to either the CB1 or CB2 cannabinoid receptors, and thus exhibits no psychotropic activity. NAGly also displays modest activity as an in vitro inhibitor of FAAH, the enzyme primarily responsible for the inactivation of anandamide under physiological conditions. We do not believe this effect results in anti-inflammatory action. However, NAGly binds with high affinity to GPR18 resulting in a robust increase of the anti-inflammatory eicosanoid PGJ. A growing body of reports indicates a wide range of functional responses for NAGly, however, none address the subject of receptor-mediated signaling pathways. An understanding of the pathways would open the way for the discovery of potent analogs of NAgly that would be candidates for therapeutic agents, which is my long-term goal.
A Novel Bioactive Lipid Mediated Signaling Pathway
Putative mechanisms for analgesic and anti-inflammatory actions of NAgly.
1. Inhibition of FAAH elevates anandamide and 2-AG levels (Burstein et al., 2002; Cascio et al., 2004; Huang et al., 2001).
2. Anandamide activates CB1 and CB2 (Axelrod et al., 1998; Barnett-Norris et al., 1998).
3. Receptor activation produces analgesia (Stein et al., 1996; Walker et al., 1999).
4. NAgly binds to PPAR-g (Burstein, 2005).
5. PPAR-g elevates COX-2 expression (Na et al., 2003).
6. COX-2 mediates PGD2 synthesis (Na et al., 2003).
7. Unregulated transformation to PGJ products (Na et al., 2003).
8. PGJ2 promotes resolution of chronic inflammation (Gilroy et al., 1999).
9. Possible positive feedback to PPAR-g (Farnesi-de-Assuncao et al., 2012)
10. NAgly binds to GPR-18 (Burstein et al.,unpublished).
11. Inhibition of forskolin-stimulated adenylate cyclase (Kohno et al., 2006).
12. Activation of phospholipases (Exton, 1996).
13. Release of free arachidonic acid (Burstein et al.,unpublished).
14. Increased lipoxin A4 and PGJ2 synthesis (Burstein et al.,unpublished).
15. Lipoxin A4 promotes resolution of chronic inflammation (Serhan, 2007).