Olivier CivelliProfessor, Pharmacology and Eric L. and Lila D. Nelson Chair in Neuropharmacology Joint Appointment, Developmental & Cell Biology Joint Appointment, Pharmaceutical Sciences Graduate Program Director/Advisor, Pharmacology & Toxicology Program, Pharmacology |
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Research Interests |
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 | ||
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Academic Distinctions |
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 |
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Research Abstract |
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. We have showed for example that orphanin FQ attenuates behavioral responses to stress. We have also shown that another neuropetide found via the orphan receptor strategy, prolactin-releasing peptide, suppresses absence seizures and promotes awakening by modulating the AMPA neurotransmission. 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 decrease food intake 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. |
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| Publications |
Representative Publications: 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. 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. (2005) GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends in Pharmacological Sciences 26:15-19. Civelli, O. (2005) An orphan GPCR adopted by a family of transmitters Molecular Pharmacology 67:1-2. Civelli, O. (2005) Orphan GPCRs in the regulation of sleep and circadian rhythm. FEBS Journal 272:5673-4. Civelli, O., Saito, Y., Wang, Z., Nothacker, HP. and Reinscheid, R. (2006) Orphan GPCRs and their ligands. Pharmacology & Therapeutics 110:525-532. Wang Z, Takahashi T, Saito Y, Nagasaki H, Ly NK, Nothacker HP, Reinscheid RK, Yang J, Chang JK, Shichiri M and Civelli O. (2006) Salusin beta is a surrogate ligand of the mas-like G protein-coupled receptor MrgA1. European Journal of Pharmacology 539:145-150. Nagasaki H, Wang Z, Jackson VR, Lin S, Nothacker HP, Civelli O (2006) Differential expression of the thyrostimulin subunits, glycoprotein alpha2 and beta5 in the rat pituitary. Journal of Molecular Endocrinology. 37:39-50. 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. Roozendaal B., Lengvilas, R., McGaugh J.L., Civelli O. and Reinscheid R.K. (2007) Orphanin FQ/nociceptin interacts with the basolateral amygdala noradrenergic system in memory consolidation. Learning and Memory 14:29-35. Dolezelova E, Nothacker HP, Civelli O, Bryant PJ and Zurovec M (2007). A Drosophila adenosine receptor activates cAMP and calcium signaling. Insect Biochem Mol Biol. 37:318-29. Clark SD, Alderson HL, Winn P, Latimer MP, Nothacker HP and Civelli O. (2007) Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum. Journal of Neurochemistry.102:112-20. Okajima Y, Nagasaki H, Suzuki C, Suga H, Ozaki N, Arima H, Hamada Y, Civelli O and Oiso Y. (2008) Biochemical roles of the oligosaccharide chains in thyrostimulin, a heterodimeric hormone of glycoprotein hormone subunits alpha 2 (GPA2) and beta 5 (GPB5). Regulatory Peptides.148:62-7. Chung S., Funakoshi T. and Civelli O. (2008) Orphan GPCR research. British Journal of Pharmacology. Suppl 1:S339-46. 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. |
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| Grants | National Institute on Drug Abuse (NIDA) R03 DA026557, 09/01/08-02/28/10, $16,393 direct costs, High-throughput assay for G-protein coupled receptors in pain research (Role: P.I.). | |
| Davis Foundation, 2009-2012, 07/01/09-06/30/12, $141,000 direct costs, The MCH system as a new target for the management of eating disorders (Role: Sponsor for Posdoctoral Fellow: Shinjae Chung). | ||
| National Institute on Drug Abuse (NIDA) R01 DA024746, to be funded beginning 12/01/09-11/30/13, $1,057,177 direct costs, A novel neuropeptide system involved in drug abse (Role: P.I.). | ||
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Professional Societies |
European College of Neuropsychopharmacology American Society for Pharmacological and Experimental Therapeutics Endocrine Society American Association of the Advancement of Science American Society for Neuroscience European Neuroscience Association Catecholamine Club American College of Neuropsychopharmacology |
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| Other Experience |
Head Department of Biology F. Hoffmann-La Roche 1992—1996 |
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| Graduate Programs |
Pharmacology and Toxicology Interdepartmental Neuroscience Program Developmental Biology and Genetics Cellular and Molecular Biosciences Medicinal Chemistry and Pharmacology |
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| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=3277 | |
| Last updated | 10/30/2009 | |