Alcohol Center for Translational Genetics (ACTG)

描述(由申请人提供)：酒精转化遗传学中心(ACTG)将确定新的蛋白质作为酒精使用障碍治疗的靶点，并将确定它们调节过量酒精摄入的机制。候选蛋白质将在酒精自我给药程序中进行评估，该程序模拟人类过度饮酒、饮酒动机和复发。解剖焦点将集中在伏隔核、杏仁核和腹侧被盖区这三个大脑区域，这些区域都在酒精消费和复发中发挥重要作用。根据当前资金周期的发现，确定H-RAS/PI3激酶AKT/mTORC1信号是乙醇消耗的关键调节因素，所有Research组件都将包括测试新蛋白与这一途径的关系的实验。三个研究项目将集中在酒精研究中新出现的蛋白质：SGK1、GSK-3和其他受mTORC1(组分4)调控的蛋白质；及其直接底物(组分5)；以及增食欲素/下克隆素受体(组分6)。行政核心(构成部分1)将管理ACTG职能。动物行为核心(组件2)将在大鼠和小鼠身上进行间歇性酒精摄入的研究，并将在大鼠可操作的自我给药程序中提供帮助。载体和成像核心(组件3)将提供最先进的服务，以生成用于转基因表达或基因沉默的病毒载体，并通过激光捕获显微切割、高分辨率免疫荧光和定量荧光原位杂交来分析转录本和蛋白质丰度，以检测树突中的mRNAs。计划开展两个试点项目。第一项研究将检验这样一种假设，即阿片受体介导的抑制GABA释放可以减少焦虑的酗酒者的饮酒量。第二项研究将确定过量饮酒诱导的NMDA受体活性上调是否有助于背内侧纹状体的长时程增强，从而增强饮酒和寻找酒精的能力。总的来说，ACTG为整合研究新的蛋白质提供了一个独特的机会，这些蛋白质可能会导致开发人类酒精使用障碍的新疗法。

DESCRIPTION (provided by applicant): The Alcohol Center for Translational Genetics (ACTG) will identify novel proteins as targets for therapeutics for alcohol use disorders and will determine mechanisms by which they act to regulate excessive ethanol intake. Candidate proteins will be evaluated in ethanol self-administration procedures that model excessive binge drinking in humans, motivation to drink ethanol, and relapse. The anatomical focus will be on 3 brain regions, the nucleus accumbens, the amygdala, and the ventral tegmental area, which all play important roles in ethanol consumption and relapse. Based on findings during the current funding cycle that identified H-Ras/PI3 kinaseAKT/mTORC1 signaling as a key regulator of ethanol consumption, all Research Components will include experiments that test the relationship of the novel proteins with this pathway. Three research projects will focus on proteins new to alcohol research: SGK1, GSK-3 and others whose translation is regulated by mTORC1 (Component 4); PKM? and its direct substrates (Component 5); and orexin/hypocretin receptors (Component 6). An Administrative Core (Component 1) will manage ACTG functions. An Animal Behavior Core (Component 2) will perform studies of intermittent ethanol access in rats and mice and will provide assistance in rat operant self-administration procedures. A Vector and Imaging Core (Component 3) will provide state-of-the art services to generate viral vectors for transgenic expression or gene silencing, and to analyze transcript and protein abundance by laser capture microdissection, high resolution immunofluorescence, and quantitative fluorescent in situ hybridization for detecting mRNAs in dendrites. Two Pilot projects are planned. The first will test the hypothesis that delta opioid receptor mediated inhibition of GABA release decreases alcohol consumption in anxious alcoholics. The second will determine whether up-regulation of NMDA receptor activity, induced by excessive ethanol consumption, facilitates long-term potentiation in the dorsomedial striatum, and thereby enhances ethanol drinking and seeking. Collectively, the ACTG provides a unique opportunity for integrated study of novel proteins that may lead to the development of new treatments for alcohol use disorders in humans.