The ultimate goal of this research is to develop a therapy for obesity based upon the identification of novel beta-adrenergic agonists which are selective stimulators of thermogenesis in humans. Atypical (non-beta-1, beta-2) beta-adrenergic receptors (beta-ARs) are thought to mediate sympathetic nervous system stimulation of thermogenesis. Atypical beta-agonists have been shown to stimulate thermogenesis and promote weight loss in animal models and in human clinical trials, but despite their relative selectivity, interactions with beta-1-AR and beta-2-AR produce side effects. Improvements in agonist selectivity for stimulation of thermogenesis would lead to useful therapeutics.
The specific aim of the proposed research plan is to establish a screening system for selective thermogenic beta-agonists. During Phase I we propose to employ polymerase chain reaction (PCR) and molecular cloning techniques to identify and isolate genes for atypical beta-ARs expressed in tissues which are sites for thermogenesis in humans. During Phase II, the genes for atypical beta-ARs will be introduced into Chinese hamster ovary (CHO) cells to establish a matrix of cell lines expressing functional atypical receptors, which will them be used to screen potential thermogenic agonists.
