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Faculty
Benjamin Cravatt
Chairman
CHEMICAL PHYSIOLOGY
TSRI - 1992
Joint Appointments
CHEMISTRY
Education
Ph.D.,The Scripps Research Institute, 1996
Research Focus
Chemical PhysiologyOur laboratory is interested in understanding complex physiology and behavior at the level of chemistry and molecules. At the center of cross talk between different physiological processes are endogenous compounds which serve as a molecular mode for intersystem communication. However, many of these molecular messages remain unknown, and even in the cases where the participating molecules have been defined, the mechanisms by which these compounds function are for the most part still a mystery. We are presently focusing our efforts on a family of chemical messengers termed the fatty acid amides, which have been shown to affect many physiological functions, including sleep, thermoregulation, pain sensitivity, and angiogenesis. In particular, one member of this family, oleamide, has been identified as a compound that accumulates selectively in the cerebrospinal fluid of tired animals, suggesting that oleamide may function as a molecular indicator of the organism's need for sleep. Indeed, upon treatment with oleamide, rats have been shown to fall asleep.
The in vivo levels of chemical messengers like the fatty acid amides must be tightly regulated to maintain proper control over their influence on brain and body physiology. We are characterizing one mechanism by which the level of fatty acid amides can be regulated in vivo, an enzyme termed fatty acid amide hydrolase (FAAH), which serves to degrade the fatty acid amides to inactive metabolites. Thus, FAAH effectively terminates the signaling messages conveyed by fatty acid amides, possibly ensuring that these molecules do not generate physiological responses in excess of their intended purpose. We are presently studying the role that FAAH plays in the dynamic regulation of fatty acid amide levels in vivo using genetic, structural, and chemical approaches.
A second major focus of our laboratory is the design and utilization of chemical probes for the global analysis of protein function. The evolving field of proteomics, defined as the simultaneous analysis of the complete protein content of given cell or tissue, is faced with considerable conceptual and technical challenges. Our efforts are aimed at enhancing the quality of information obtained from proteomics experiments by utilizing chemical probes that read out the collective catalytic activities of entire classes of enzymes. These probes would thus serve as a means of recording variations in protein function independent of alterations in protein abundance, offering a potentially powerful and complimentary set of tools for proteome analysis. We have succeeded in generating one such chemical reagent, FP-biotin, that targets the serine hydrolases, a large family of enzymes composed of numerous protease, lipases, esterases, and amidases. We are currently using FP-biotin to explore the roles that serine hydrolases play in variety of physiological and pathological processes. Additionally, in an ongoing collaboration with the Sorensen research group, we are designing and testing chemical probes that target other enzyme families in order to expand our capacity to profile proteins in an activity-based manner.
Selected References
Adam, G.C., Cravatt, B.F., Sorensen, E.J. "Profiling the Specific Reactivity of the Proteome with Non-Directed Activity-Based Probes." Chem. Biol. 2001, 8, 81-95.
Kidd, D. Liu, Y., Cravatt B.F. "Profiling Serine Hydrolase Activities in Complex Proteomes." Biochemistry 2001, 40, 4005-4015.
Patricelli, M.P., Cravatt, B.F. "Characterization and Manipulation of the Acyl Chain Selectivity of Fatty Acid Amide Hydrolase." Biochemistry 2001, 40, 6107-6115.
Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R., Lichtman, A.H. "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase." Proc Natl Acad Sci U S A. 2001 98, 9371-9376.
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