DO GENES & BRAIN ACTIVITY PREDICT ALCOHOL RISK?

申请人摘要：我的总体职业目标将通过此实现 K23奖是学习如何整合药理学，分子遗传学， 神经影像学技术在药物开发和评估中的应用 治疗酒精中毒 为了实现我的目标，成为一名独立的医生科学家， 在K23奖励期结束后，对我来说， 作为一个普通的院士，并获得具体的分专业培训。 我 分专业培训将在一个综合的伞下组织， 神经科学项目组织为三个实验，需要知识和 药理学、神经影像学和分子生物学等学科的专业知识 遗传学 我的项目是基于对肾上腺素能功能的理解， 重度社交饮酒者饮酒行为的决定因素 前提是 假设肾上腺素能功能是在遗传控制下， 5-羟色胺转运蛋白（SERT）的5 ′-侧翼调节区（5 ′-HTTPLR）， 我将研究如何个人与长（LL）的形式，与多达三次 突触内5-羟色胺（5-HT）的摄取增加，因此相对 低能状态比那些与短或杂合形式（SS/SL）， 不同的是他们对酒精或渴望的享乐效应的理解能力 在人类实验室里，当实验者产生线索时， 我会用色氨酸刺激肾上腺素能系统 耗尽范式，以确定是否改变5-HT的可用性 加剧了基因型导致的功能和行为差异 在SERT的变化。我将使用单光子发射计算机 断层扫描（SPECT），以证明个人与LL形式比较， 与SS/SL变种增加了SERT密度，一个指数， 5-HT系统的功能能力，在个人与这些各自 基因型如果这些实验成功了，我就能证明 重度社交饮酒者之间的基因型差异可能与 酒精中毒疾病的不同风险。 因此，这项研究 有可能确定一种方法来界定重度社交饮酒者 酒精中毒的风险最大，应该指导 合理开发治疗糖尿病的特异性肾上腺素能药物 酒精中毒

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.