Alcohol Center for Translational Genetics (ACTG)

酒精转化遗传学中心(ACTG)将有两个主要主题。第一个将是研究新的蛋白质，以确定它们或它们参与的信号通路是否包含治疗酒精使用障碍的潜在药物靶点。ACTG的另一个主题将是调查编码这些蛋白质的基因是否与人类酗酒的风险有关。它们参与的蛋白质和信号通路将从正在进行的无脊椎动物基因筛查或体外和体外研究中选择。这种方法是基于一个耐人寻味的假设，即基因 在这些模型系统中发现的基因与人类酗酒有关。在无脊椎动物、培养的神经细胞和啮齿动物中，PKA和PKC介导的信号以及特定的多肽和离子通道在酒精行为反应中的重要性的研究在一定程度上证实了这一假设。候选蛋白质将在大鼠和小鼠的行为模型中得到验证，这些模型测量对急性酒精暴露或药物自我给药和奖励的反应水平。人类中的等位基因变异将被识别出来，这些变异被预测会改变基因表达或蛋白质功能，并增加罹患 人类中的酒精中毒。四个研究组成部分、四个核心组成部分和一个试点项目组成部分涉及这些主题。三个研究项目将集中于深入研究酒精研究界在小鼠和大鼠中新发现的基因：H-RAS(组分5)、MUNC-79(组分6)和陶氏蛋白激酶(组分7)。第四个研究项目(组成部分8)将确定这些基因和相关基因在人类中的变异，并进行研究以检查它们的功能意义。除了一个管理ACTG职能的行政核心(构成部分1)外，还将有三个科学核心。一种动物和行为 CORE(构成部分2)将为所有使用小鼠的研究项目建立标准化的行为研究小组，并将为ACTG提供小鼠育种和基因分型服务，并协助进行复杂的行为研究。转基因和成像核心(组件3)将提供最先进的服务，以产生针对基因的小鼠和病毒载体，用于表达转基因或通过RNA干扰在大鼠和小鼠中使基因沉默。基因组学核心(组成部分4)将提供高通量测序能力、生物信息学工具和支持，以及定量RT-PCR的协助。两个试点项目将 对涉及大鼠非典型蛋白激酶C同工酶、果蝇MAP激酶磷酸酶和果蝇BMP2/4同源物的新蛋白质和途径进行早期研究。总的来说，ACTG将为跨物种的新基因的详细研究提供一个独特的中心，这些新基因可能会导致开发预防和治疗人类酒精使用障碍的新方法。

The Alcohol Center for Translational Genetics (ACTG) will have two major themes. The first will be to study novel proteins to determine whether they or the signaling pathways in which they participate contain potential drug targets for treating alcohol use disorders. The other main theme of the ACTG will be to investigate whether the genes that encode these proteins are associated with risk of alcoholism in humans. The proteins and signaling pathways in which they participate will be chosen from ongoing invertebrate genetic screens or ex vivo and in vitro studies. The approach is based on the intriguing hypothesis that genes identified in these model systems have relevance for human alcoholism. This hypothesis has been validated, in part, by studies demonstrating the importance of PKA- and PKC-mediated signaling, and specific peptides and ion channels in behavioral responses to alcohol in invertebrates, cultured neural cells and rodents. Candidate proteins will be validated in rat and mouse behavioral models that measure either the level of response to acute ethanol exposure or drug self-administration and reward. Allelic variants in humans will be identified that are predicted to alter gene expression or protein function and confer risk of alcoholism in humans. Four research components, four core components, and a pilot project component address these themes. Three research projects will focus on intensively studying genes novel to the alcohol research community in mice and rats: H-Ras (Component 5), munc-79 (Component 6), and Tao kinases (Component 7). A fourth research project (Component 8) will identify variants of these and related genes in humans and, perform studies to examine their functional significance. In addition to an Administrative Core (Component 1) to manage ACTG functions, there will be three Scientific Cores. An Animal and Behavior Core (Component 2) will establish a standardized battery of behavioral studies for all research projects using mice, and will provide mouse breeding and genotyping services and assistance with complex behavioral studies for the ACTG. A Transgenic and Imaging Core (Component 3) will provide state-of-the art services for generating gene-targeted mice and viral vectors for expression of transgenes or gene silencing by RNA interference in rats and mice. A Genomics core (Component 4) will provide high-throughput sequencing capability, bioinformatics tools and support, and assistance with quantitative RT-PCR. Two Pilot projects will perform early studies of novel proteins and pathways involving atypical protein kinase C isozymes in rats, a Drosophila MAP kinase phosphatase, and a Drosophila BMP2/4 homolog. Collectively, the ACTG will provide a unique center for the detailed study across species of novel genes that may lead to the development of new approaches for preventing and treating alcohol use disorders in humans.