Novel Genes Involved in Drug Response

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DESCRIPTION: (provided by the applicant) Nicotine is the most addictive drug abused worldwide. On average over 430,000 Americans die each year from nicotine-related illnesses. A long-term goal of our research is to identify novel genes involved in mediating the effects of nicotine on human health to identify new target sites to develop medications to help people stop smoking. The largest portion of nicotine-related deaths is the result of cardiovascular failure due to high blood pressure and increased heart rate. Short-term administration of nicotine typically raises human heart rate by l0-25 bpm. The role of the central nervous system in mediating the effect of nicotine is not well understood. Although nicotine is known to act through catecholamines, blood pressure and heart rate rise before catecholamine levels, increase. Thus, molecules other than catecholamines, in part, mediate the effects of nicotine on cardiovascular parameters. Drosophila melanogaster is an established model organism for human drug addiction and cardiovascular research. We have developed an in vivo assay and determined that nicotine increases adult D. melanogaster heart rate. Our hypothesis is that P element disruption of a gene whose product mediates the effect of nicotine on the cardiovascular system will have an altered heart rate in response to this drug. To identify gene products involved in transducing the effect of nicotine on heart rate, we will (aim #1) analyze P element D. melanogastar insertion mutants. To verify the role of a gene product in mediating the effect of nicotine, we will (aim #2) generate a revertant of the mutant. A revertant in which the P element no longer resides in a gene will display a wild type phenotype when exposed to nicotine. To confirm the role of the candidate gene product, we will (aim #3) locate the P element insertion site to identify the altered gene. We will search for mammalian orthologs of the D. melanogaster gene products identified in our P element screen. Our future work will apply physiological and molecular genetic techniques in mouse to delineate the role of these novel molecules in transducing the effect of nicotine in mammals. Ultimately, our research will determine the role of these gene products in mediating the effect of nicotine in humans.