Novel Genes Involved in Drug Response

描述：(申请人提供) 尼古丁是全世界最容易上瘾的毒品。平均超过430,000 美国人每年死于与尼古丁有关的疾病。一个长期目标是 我们的研究是为了找出新的基因，这些基因参与调节 尼古丁对人类健康的影响确定开发药物的新靶点 帮助人们戒烟。 尼古丁相关死亡的最大部分是心血管疾病造成的。 由于高血压和心率加快而导致的衰竭。短期 服用尼古丁通常会使人的心率增加10-25次/分。这个 中枢神经系统在调节尼古丁效应中的作用不是 很好理解。虽然已知尼古丁通过儿茶酚胺起作用， 血压和心率在儿茶酚胺水平升高之前就会升高。因此， 儿茶酚胺以外的其他分子部分参与了尼古丁的作用。 对心血管参数的影响。 黑腹果蝇是人类药物的既定模式生物 成瘾和心血管研究。我们已经开发了一种体内测试方法， 确定尼古丁会增加成年黑腹果蝇的心率。我们的 假说是基因的P元件中断，其产物介导 尼古丁对心血管系统的影响会改变心率 作为对这种药物的反应。鉴定与转导细胞有关的基因产物 尼古丁对心率的影响，我们将(目标1)分析P元素D。 黑素胃星插入突变体。为了验证基因产物在基因中的作用 通过调节尼古丁的作用，我们将(目标2)产生一种可逆性的 变种人。P元素不再存在于基因中的返回体将 当暴露在尼古丁中时，表现出野生型。确认…的作用 候选基因产物，我们将(目标3)定位P元件插入 站点来识别改变后的基因。 我们将寻找与黑腹果蝇基因产物同源的哺乳动物。 在我们的P元素屏幕上识别。我们未来的工作将应用生理学 以及分子遗传学技术在小鼠中所扮演的角色 在哺乳动物中传递尼古丁效应的分子。最终，我们的 研究将确定这些基因产物在调节这种效应中的作用。 尼古丁在人体内的含量。

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.