DO GENES & BRAIN ACTIVITY PREDICT ALCOHOL RISK?

应聘者摘要：我的首要职业目标是通过这个 K23奖是学习如何将药理学、分子遗传学和 神经成像技术在治疗药物开发和评估中的应用 酒精中毒的治疗。 为了实现我成为一名独立内科科学家的目标 K23获奖期结束，对我来说，掌握熟练程度是很重要的 作为一名普通院士并获得特定的分专业培训。我的 分专业培训将在一个综合的 神经科学项目由三个实验组成，需要知识和 在药理学、神经成像和分子科学领域具有专业知识 遗传学。 我的项目是基于对5-羟色胺能功能作为 社交酗酒者饮酒行为的决定因素。谓词基于 5-羟色胺能功能受基因控制的假说 5-羟色胺转运体(SERT)5‘侧翼调控区(5’-HTTPLR) 我会研究个人如何用Long(LL)形式，最多用三次 突触内5-羟色胺(5-HT)的更大摄取因此是一种 与短型或杂合型(SS/SL)相比， 在欣赏酒精或贪婪的享乐效果的能力上有所不同 因为当被实验者激怒时，它会在人体实验室中产生线索。 我会用色氨酸从药理上刺激5-羟色胺能系统 耗竭范式，以确定5-羟色胺可用性的变化 加剧因基因分型而导致的功能和行为差异 SERT的变异。我将使用计算机化的单光子发射 断层扫描(SPECT)显示个体与LL形态比较 随着SS/SL变体的增加，SERT密度增加，这是 这些个体5-羟色胺系统的功能能力 基因分型。如果这些实验成功，我或许能够证明 大量社交饮酒者之间的基因差异可能与 发展成酒精中毒性疾病的不同风险。因此，这项研究 有可能找到一种方法来描述社交酗酒者 有最大风险发展成酒精中毒性疾病，并应引导 合理开发治疗慢性阻塞性肺疾病的特异性5-羟色胺能药物 酗酒。

APPLICANT'S ABSTRACT: My overarching career goal to be achieved through this K23 award is to learn how to integrate pharmacological, molecular genetic, and neuroimaging techniques in the development and assessment of medications for the treatment of alcoholism. To accomplish my goal of becoming an independent physician scientist at the conclusion of the K23 award period, it is important for me to gain proficiency as a general academician and to obtain specific sub-specialty training. My sub-specialty training will be organized under the umbrella of an integrated neuroscience project organized as three experiments requiring knowledge and expertise with the disciplines of pharmacology, neuroimaging, and molecular genetics. My project is based upon understanding the role of serotonergic function as a determinant of drinking behavior in heavy social drinkers. Predicated on the hypothesis that serotonergic function is under genetic control at the 5'-flanking regulatory region (5'-HTTPLR) of the serotonin transporter (SERT), I will study how individuals with the long (LL) form, with up to three times greater uptake of intrasynaptic serotonin (5-HT) and therefore a relative hyposerotonergic state than those with the short or heterozygous form (SS/SL), differ in their ability to appreciate the hedonic effects of alcohol or crave for it when provoked by experimenter generated cues in the human laboratory. I will pharmacologically provoke the serotonergic system, using the tryptophan depletion paradigm, to determine whether alterations in 5-HT availability exacerbates the functional and behavioral differences due to genotypic variation at the SERT. I will use Single Photon Emission Computerized tomography (SPECT) to demonstrate that individuals with the LL form compared with the SS/SL variants have increased SERT density, an index of the functional capacity of the 5-HT system in individuals with these respective genotypes. If these experiments are successful, I may be able to show that genotypic differences between heavy social drinkers can be associated with differential risks of developing the alcoholism disease. This study therefore has the potential to identify a method for delineating heavy social drinkers with the greatest risk for developing the alcoholism disease, and should guide the rational development of specific serotonergic agents for the treatment of alcoholism.