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.
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