Novel Genes Involved in Drug Response

描述：（申请人提供） 尼古丁是全世界滥用的最容易上瘾的药物。平均超过43万人 美国人每年死于与尼古丁有关的疾病。的长期目标 我们的研究是确定新的基因参与介导的影响， 尼古丁对人体健康的影响，以确定新的目标网站，以开发药物， 帮助人们戒烟。 尼古丁相关死亡的最大部分是心血管疾病 由于高血压和心率加快而导致的衰竭。短期 尼古丁的施用通常使人的心率提高10 -25 bpm。的 中枢神经系统在调节尼古丁作用中的作用不是 很好理解。虽然已知尼古丁通过儿茶酚胺起作用， 血压和心率上升前，儿茶酚胺水平增加。因此，在本发明中， 除了儿茶酚胺之外的分子，部分地介导尼古丁的作用 关于心血管参数 黑腹果蝇是一种已建立的人类药物模型生物 成瘾和心血管研究。我们已经开发了一种体内测定法， 确定尼古丁增加成人D。黑胃心率我们 一种假说是，其产物介导 尼古丁对心血管系统的影响会改变心率 对这种药物的反应。为了鉴定参与转导的基因产物， 尼古丁对心率的影响，我们将（目的#1）分析P元素D。 melanogastar插入突变体。为了验证基因产物在 为了介导尼古丁的作用，我们将（目标#2）产生尼古丁的回复突变体。 变种人一个P元件不再存在于基因中的回复突变体， 当暴露于尼古丁时显示野生型表型。确认的作用 候选基因产物，我们将（目标#3）定位P元件插入 以识别改变的基因。 我们将寻找D.黑胃基因产物 在我们的P元素屏幕中识别。我们未来的工作将应用于生理 和分子遗传技术在小鼠中的作用，以描绘这些新的 分子在哺乳动物中传递尼古丁的作用。最终，我们 研究将确定这些基因产物在介导效应中的作用。 尼古丁在人体内

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.