Chair and Professor, Pharmacology and Eric L. and Lila D. Nelson Chair in Neuropharmacology
Joint Appointment, Developmental & Cell Biology
Joint Appointment, Pharmaceutical Sciences
|Molecular neurobiology, G protein-coupled receptors, Neuropeptides, Orphan receptors, Novel neurotransmitters, Dopamine receptors, Orphanin FQ/nociceptin, MCH, Urotensin II, Novel transmitters|
|URLs||Pharmacology Home Page|
|Dr. Civelli's Lab|
|See below for selected publications or click here for additional publication listings available via PubMed|
1989, Pfizer traveling fellow award, Clinical Research Institute of Montreal
1991, Lecturer in the "Distinguished Speaker Series" of the Department of Pharmacology, University of Toronto
1992, Presidential Lecture, Annual Meeting of the Society for Neuroscience
1992, Robert and Adele Blank Lectureship, New York University Medical Center
2002, Athalie Clarke Research Award, University of California, Irvine
2004, Interviewed by Nature Drug Discovery as one of the 20 world’s leading experts on GPCR research (Nature Drug Discovery 3: 575-626)
2006, ISI Highly Cited Researcher
2010, NARSAD Distinguished Investigator Award
The main focus of our research aims at furthering our understanding of the diversity of brain function by identifying and studying novel molecules which mediate synaptic transmission. Synaptic transmission is the mechanism which underlies the biochemical reactions that make brain functions and relies on the recognition of neurotransmitters and neuropeptides by their specific receptors. From genomic analyses we evaluate that we now know only a portion of all the transmitters that direct brain function. Our aim is to isolate novel neurotransmitters or neuropeptides and to study their physiological implications.
Among the receptors that direct brain functions, the most numerous are the G protein-coupled receptors (GPCRs). Among all the GPCRs that have been cloned some do not bind any of the presently known neurotransmitters or neuropeptides, these are the "orphan" GPCRs. We believe that these orphan receptors recognize thus far undescribed transmitters. This led us to use orphan GPCRs as targets for the identification and isolation of their specific natural ligands, that they purify from brain extracts. The natural ligands are then characterized biochemically, pharmacologically and physiologically to demonstrate that they are novel neurotransmitters or neuropeptides. We were the first in 1995 to ever isolate a novel ligand through this approach and isolated and characterized the neuropeptide orphanin FQ or nociceptin. Since then, this approach has been used around the world to identify the receptors of a dozen of new neuropeptides.
The second phase of our studies consists in determining the biological significance of the novel neurotransmitters or neuropeptides. Toward this goal, we define the novel neurotransmitters and neuropeptides tissue distribution and neuronal pathways. We then determine, by administering the novel neurotransmitters or neuropeptides to animals, whether they affect behavior and which particular responses are modulated. Because neurotransmitters and neuropeptides can have a broad spectrum of effects, this part of our approach is often open-ended and is therefore combined to two different approaches. The first one is to engineer strains of mice genetically devoid of the novel neurotransmitter or neuropeptide and to compare the genetically-altered mice in the absence or upon the addition of the novel neurotransmitter or neuropeptide. The second one is to screen for molecules (antagonists or agonists) that can be used in behavioral experiments in controlled conditions. For example, we have recently shown that a synthetic molecule is able to reduce schizophrenic-like symptoms in animal models by blocking a recently-deorphanized GPCR system.
Together these studies lead us towards the ultimate goal of our research, to find out whether the novel neurotransmitter or neuropeptide systems can be of use in treating human disorders.
29 Patents Issued.
Bunzow, J.R., Van Tol, H.H., Grandy, D.K., Albert, P., Salon, J., Christie, M., Machida, C., Neve, K.A. and Civelli, O. (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature, 336:783-787
Zhou, Q.Y., Grandy, D.K., Thambi, L., Kushner, J., Van Tol, H.H.M., Cone, R., Pribnow, D., Salon, J., Bunzow, J.R. and Civelli, O. (1990) Cloning and expression of human and rat D1 dopamine receptors. Nature, 347:76-80.
Van Tol, H.H.M., Bunzow, J.R., Guan, H.C., Sunahara, R.K., Seeman, P., Niznik, H.B. and Civelli, O. (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature, 350:610-614
Grandy, D.K., Zhang, Y., Bouvier, C., Zhou, Q.Y., Johnson, R.A., Allen, L., Buck, K., Bunzow, J.R., Salon, J. and Civelli, O. (1991) Multiple human D5 dopamine receptor genes: A functional receptor and two pseudogenes. Proceedings of the National Academy of Sciences, USA, 88:9175-9179.
Reinscheid, R.K., Nothacker, H.P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J.R., Grandy, D.K., Langen, H., Monsma, F.J. and Civelli, O. (1995) Orphanin FQ: A neuropeptide that activates an opioid-like G protein-coupled receptor. Science, 270:792-794.
Saito, Y., Nothacker, H.P., Wang, Z., Lin, S.H.S., Leslie, F. and Civelli, O. (1999) Molecular characterization of the melanin-concentrating hormone receptor. Nature, 400:265-269.
Nothacker, H.P., Wang, Z., McNeill, A.M., Saito, Y., Merten, S., O’Dowd, B., Duckles, S.P. and Civelli, O. (1999) Identification of the natural ligand of an orphan G protein-coupled receptor involved in the regulation of vasoconstriction. Nature Cell Biology, 1:383-385.
Civelli, O., Nothacker, H.P., Saito, Y., Wang, Z., Lin, S.H.S., and Reinscheid R.K. (2001) Novel neurotransmitters as natural ligands of orphan G protein-coupled receptors. Trends in Neuroscience 24:230-237.
Xu, Y.L., Reinscheid, R.K., Huitron-Resendiz, S., Clark, S.D., Wang, Z, Lin, S.H., Brucher, F.A., Zeng, J., Ly, N.K, Henriksen, S.J., de Lecea, L., and Civelli, O. (2004). Neuropeptide S: a novel neuropeptide promoting arousal and anxiolytic-like effects Neuron 43:487-497.
Civelli, O., Saito, Y., Wang, Z., Nothacker, HP. and Reinscheid, R. (2006) Orphan GPCRs and their ligands. Pharmacology & Therapeutics 110:525-532.
Xu, Y.L., Gall, C.M., Jackson, V.R., Civelli, O. and Reinscheid, R.K. (2007) Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. Journal of Comparative Neurology 500:84-102.
Book editor: Orphan G protein-coupled receptors and novel neuropeptides (2008) Results and Problems in Cell Differentiation. 46, Springer Verlag, Berlin.
Nagasaki H., Chung S., Dooley C.T., Wang Z., Li C., Saito Y., Clark S.D., Houghten R.A. and Civelli O (2009) The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries. European Journal of Pharmacology 602:194-202.
Chung S., Hopf F.W., Nagasaki H., Li CY., Belluzzi J.D., Bonci A. and Civelli O. (2009) The melanin-concentrating hormone system modulates cocaine reward. Proceedings National Academy of Sciences, USA 106(16):6772-6777.
Chung, S., Verheij, M.M., Hesseling, P., van Vugt, R.W., Buell, M., Belluzzi, J.D., Geyer, M.A., Martens, G.J. and Civelli O. (2011) The Melanin-Concentrating Hormone (MCH) System Modulates Behaviors Associated with Psychiatric Disorders PLoS One. 2011;6(7):e19286. Epub 2011 Jul 19.
|Grant||National Institute on Drug Abuse (NIDA) R01 DA024746, 02/01/10-01/31/14, $1,033,372 direct costs, A novel neuropeptide system involved in drug abuse (Role: P.I.).|
European College of Neuropsychopharmacology
American Society for Pharmacological and Experimental Therapeutics
American Association of the Advancement of Science
American Society for Neuroscience
European Neuroscience Association
American College of Neuropsychopharmacology
Chair, Department of Pharmacology
School of Medicine, UC Irvine 2011—pres
F. Hoffmann-La Roche, AG 1992—1996
Interdepartmental Neuroscience Program
Developmental Biology and Genetics
Cellular and Molecular Biosciences
Medicinal Chemistry and Pharmacology
|Link to this profile||http://www.faculty.uci.edu/profile.cfm?faculty_id=3277|