Biochemical and Genetic Determinants of Alcohol Consumption

描述(申请人提供)：这个项目是基于INIA-West的研究，显示了酒精摄入的动物模型和人类酗酒者大脑中神经免疫基因表达的变化。我们发现，六个INIA候选神经炎性基因中的任何一个的缺失都会减少酒精摄入量，而免疫信号的激活会增加酒精摄入量。这些数据表明，在人类酒精中毒和我们的遗传动物模型中，大脑中的促炎信号存在错误调节。我们的几个候选基因是一个特定的Toll样受体(TLR4)信号通路的一部分，我们将从行为和生化方面进行研究。具体目标1将：定义TLR4信号的分子成分，这些分子成分负责促进过度饮酒。这些研究将使用缺乏该系统关键组件的零突变小鼠。神经炎症信号也是酒精中毒药物开发的潜在靶点，我们将测试三种抗炎药物：米诺环素、吡格列酮和AE1-329。具体目标2将：确定小鼠因过量饮酒和神经免疫激活而受到干扰的基因网络，并将这些与人类酒精中毒的基因表达变化进行比较。这一目标还将通过测量服用减少酒精消耗的抗炎药物治疗的小鼠大脑中的细胞因子水平，来确定与酒精消费调节相关的脑细胞因子的变化。特殊目的3是一个核心功能，它将为使用RNAi、条件零突变小鼠和药理学方法的其他INIA项目提供新的INIA候选基因的行为测试。INIA相互作用：小鼠的遗传操作将使用来自Lasek和Homanics INIA核心的RNAi和零突变小鼠。我们将为Heberlein和Ponomarev项目提供行为测试，并对Ponomarev治疗小鼠。我们将与梅菲尔德和波诺马廖夫项目合作，比较我们的基因表达谱(人类和老鼠)数据、罗伯茨/科斯滕核心药物测试数据以及Siggins和Morrisett电生理学项目数据。 与公共卫生相关：酒精中毒(酒精依赖)是代价最高、危害最大的慢性病之一。治疗选择有限，而且所有治疗方法的复发率都很高。我们的初步结果表明，脑神经炎症信号可能会促进持续和过度饮酒。大脑中的神经炎性通路可能是药物开发的未知靶点，以减少过度饮酒和防止复发。

DESCRIPTION (provided by applicant): This project is based on INIA-West studies showing changes in neuroimmune gene expression in animal models of alcohol intake and in brain of human alcoholics. We found that deletion of any of six INIA candidate neuroinflammatory genes decreased alcohol consumption and activation of immune signaling increased alcohol consumption. These data suggest that in human alcoholism and in our genetic animal models there is a misregulation of pro-inflammatory signaling in brain. Several of our candidate genes are part of a specific toll-like receptor (TLR4) signaling pathway that we will study behaviorally and biochemically. Specific Aim 1 will: Define the molecular components of TLR4 signaling that are responsible for promotion of excessive alcohol consumption. These studies will use null mutant mice lacking key components of this system. Neuroinflammatory signaling is also a potential target for medication development for alcoholism and we will test three anti-inflammatory drugs: Minocycline, Pioglitazone and AE1-329. Specific Aim 2 will: Define the gene networks that are perturbed by excessive alcohol consumption and neuroimmune activation in mouse and compare these to gene expression changes in human alcoholism. This aim will also define changes in brain cytokines related to regulation of alcohol consumption by measuring cytokine levels in brain of mice treated with anti-inflammatory drugs which reduce alcohol consumption. Specific Aim 3 is a Core function that will provide behavioral testing of new INIA candidate genes for other INIA projects using RNAi, conditional null mutant mice and pharmacological approaches. INIA Interactions: Genetic manipulation In mice will use RNAi and null mutant mice from the Lasek and Homanics INIA cores. We will provide behavioral testing for the Heberlein and Ponomarev projects and treated mice to Ponomarev. We will collaborate with the Mayfield and Ponomarev projects to compare our data for gene expression profiling (human and mouse), the Roberts/Kosten cores for medication testing and the Siggins and Morrisett projects for electrophysiology. PUBLIC HEALTH RELEVANCE: Alcoholism (alcohol dependence) is one of the most expensive and damaging chronic diseases. Treatment options are limited, and there is a high rate of relapse for all treatments. Our preliminary results suggest that brain neuroinflammatory signals may promote persistent and excessive alcohol consumption. Neuroinflammatory pathways in brain may be unexplored targets for medication development to reduce excessive alcohol consumption and prevent relapse.