The objective of this proposal is to understand the catalytic, structural, and cell biological features of fatty acid amide hydrolase (FAAH), a mammalian membrane-bound enzyme responsible for the catabolism of the fatty acid amide family of endogenous signaling lipids. Representative fatty acid amides degraded by FAAH include the endocannabinoid anandamide and the sleep-inducing lipid oleamide. Fatty acid amides have been shown to induce a remarkable array of pharmacological effects in mammals, including sleep, analgesia, hypothermia, and learning and memory defects. The impressive bioactivity of fatty acid amides suggests that FAAH might serve as an attractive target for therapeutic efforts aimed at influencing pain, sleep, and memory systems. The elucidation of FAAH's catalytic, structural, and cellular features would provide a foundation for the design of FAAH-specific chemical inhibitors to be employed as agents for both the study of fatty acid amide-based physiological processes and the potential pharmaceutical treatment of pathologies associated with these systems. In this application, the molecular and cellular properties of FAAH will be examined using a multidisciplinary approach, employing biochemistry, molecular biology, immunochemistry, and synthetic chemistry techniques towards the goals of determining: 1) the catalytic mechanism and origins of substrate selectivity for FAAH-mediated amide hydrolysis, 2) the x-ray crystal structure of a FAAH-oleyl phosphonate inhibitor complex, 3) the domains of FAAH responsible for self-association and membrane binding, and 4) the cellular and subcellular localization of FAAH in mammalian tissue. These proposed studies should provide molecular tools for the chemical and genetic regulation of FAAH in vivo, allowing for a direct evaluation of the potential costs and benefits of therapeutic strategies that target the endocannabinioid system for the treatment of pain, sleep, and/or mood disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Rapaka, Rao
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Scripps Research Institute
La Jolla
United States
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Sipe, Jack C; Arbour, Nathalie; Gerber, Alexandra et al. (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78:231-8
Gulyas, A I; Cravatt, B F; Bracey, M H et al. (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20:441-58
Chiang, Kyle P; Gerber, Alexandra L; Sipe, Jack C et al. (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:2113-9
Cravatt, Benjamin F; Lichtman, Aron H (2003) Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 7:469-75
Clement, Angela B; Hawkins, E Gregory; Lichtman, Aron H et al. (2003) Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J Neurosci 23:3916-23
Leung, Donmienne; Hardouin, Christophe; Boger, Dale L et al. (2003) Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nat Biotechnol 21:687-91
McKinney, Michele K; Cravatt, Benjamin F (2003) Evidence for distinct roles in catalysis for residues of the serine-serine-lysine catalytic triad of fatty acid amide hydrolase. J Biol Chem 278:37393-9
Lichtman, Aron H; Hawkins, E Gregory; Griffin, Graeme et al. (2002) Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302:73-9
Sipe, Jack C; Chiang, Kyle; Gerber, Alexandra L et al. (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci U S A 99:8394-9
Waleh, N S; Cravatt, B F; Apte-Deshpande, A et al. (2002) Transcriptional regulation of the mouse fatty acid amide hydrolase gene. Gene 291:203-10

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