Obesity has now become a significant health problem. Obesity is the result of an imbalance in the system that maintains the homeostasis between energy used and energy stored. This system relies on sensing signals originating in the energy stores located in the periphery. The peripheral signals converge into the CMS, in the hypothalamus where they are integrated and where the direction and magnitude of the efferent responses are determined. Several neuropeptides play major roles in integrating the peripheral signals in the hypothalamus in particular the bombesin-like peptides. These neuropeptides activate three receptors but one, called the BRS-3 receptor, is the one that has the most pronounced effect on feeding behavior. Mice devoid of BRS-3 receptor are hyperphagic and show increased feeding efficiency. They represent a model system for late onset obesity. There is therefore a need to study the effects that BRS-3 system has in vivo in rodents. This is however not possible because there exist no pharmacological assay that would allow to identify a ligand that could activate or inhibit the BRS-3 receptor at present. The bombesin-like peptides activate poorly BRS-3 and cannot be used in vivo. Moreover the natural ligand of the BRS-3 receptor is unknown. We therefore propose to help palliate this lack by establishing screening assays that can be used to isolate synthetic agonists or antagonists in order to study the BRS-3 system. We will first take advantage of a synthetic peptide that has high affinity for the human BRS-3 receptor, but that does not activate the rat BRS-3, to establish screening assays for the human BRS-3 receptor. These assays will be devised to allow for monitoring either receptor reactivity or receptor binding. We will then pursue to completion our preliminary studies that indicate that we are able to identify the natural ligand of the rat BRS-3 receptor. We will finally use this ligand to establish rat and mouse specific screening assay.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070619-02
Application #
7069978
Study Section
Special Emphasis Panel (ZRG1-BST-F (02))
Program Officer
Sechi, Salvatore
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$209,973
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Parks, Gregory S; Wang, Lien; Wang, Zhiwei et al. (2014) Identification of neuropeptide receptors expressed by melanin-concentrating hormone neurons. J Comp Neurol 522:3817-33
Parks, Gregory S; Okumura, Sean M; Gohil, Krupa et al. (2010) Mice lacking Melanin Concentrating Hormone 1 receptor are resistant to seizures. Neurosci Lett 484:104-7
Zhang, Li; Nothacker, Hans-Peter; Wang, Zhiwei et al. (2009) Pharmacological characterization of a selective agonist for bombesin receptor subtype-3. Biochem Biophys Res Commun 387:283-8
Civelli, Olivier (2008) The orphanin FQ/nociceptin (OFQ/N) system. Results Probl Cell Differ 46:1-25
Chung, S; Funakoshi, T; Civelli, O (2008) Orphan GPCR research. Br J Pharmacol 153 Suppl 1:S339-46
Xu, Yan-Ling; Gall, Christine M; Jackson, Valerie R et al. (2007) Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. J Comp Neurol 500:84-102
Nagasaki, Hiroshi; Wang, Zhiwei; Jackson, Valerie R et al. (2006) Differential expression of the thyrostimulin subunits, glycoprotein alpha2 and beta5 in the rat pituitary. J Mol Endocrinol 37:39-50
Jackson, Valerie R; Nothacker, Hans-Peter; Civelli, Olivier (2006) GPR39 receptor expression in the mouse brain. Neuroreport 17:813-6
Wang, Zhiwei; Takahashi, Toshio; Saito, Yumiko et al. (2006) Salusin beta is a surrogate ligand of the mas-like G protein-coupled receptor MrgA1. Eur J Pharmacol 539:145-50
Civelli, Olivier; Saito, Yumiko; Wang, Zhiwei et al. (2006) Orphan GPCRs and their ligands. Pharmacol Ther 110:525-32

Showing the most recent 10 out of 11 publications