The development of new drugs is an expensive process that requires extensive testing of a drug's mechanism of action and safety. Although many compounds are designed for the ability to exert a desired biological effect, few perform satisfactorily as drugs due to unexpected modes of action in vivo. The investigators have developed a battery of retrovirus-based technologies that allow for the isolation of genes based on their function in tissue culture cells. The investigators state that in the Phase I proposal they have taken advantage of the inhibition of cellular proliferation by anti-hypertensive calcium channel blockers to isolate gene products that are important to the action of these drugs. They also state that preliminary studies have demonstrated the feasibility of employing this approach on a large scale to identify gene products involved in calcium physiology and cell proliferation control. In this application they propose to carry out exhaustive screens for genes that confer resistance to dihydropyridine calcium channel blockers from diverse tissue types, to categorize these gene products with respect to mechanism of drug resistance, and to identify relevant drug targets among them.
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