Integrative Neuroscience Initiative on Alcoholism

项目总结 这是针对酒精中毒的综合神经科学倡议(INIA)的竞争性续签申请- 神经免疫联盟(通知#RFA-AA-16-004/005/006)，基于基因组识别药物靶点， 与过量饮酒相关的细胞和行为神经适应。INIA神经免疫(INIA- N)将涉及NIAAA的几个目标，包括：1)了解基因组学、电生理学和 脑免疫通路的药理学及其在酒精使用障碍(AUDS)中的作用；2)使用新的 研究过度饮酒涉及的神经回路的技术；3)提高数据的重复性 以及通过在多个物种(包括人类)、多个实验室和多个 化验；4)使用新兴的计算资源，将基因网络与药物联系起来，以识别 有可能减少过度饮酒的化合物。INIA-N的一个关键目标是探索跨物种 基因组数据集，以及新的计算方法，以预测FDA批准的药物 被重新用于治疗AUDS。INIA-N的总体假设是过量饮酒会导致 在免疫相关通路中的遗传变化和神经适应 物种(包括人类)，允许系统地选择和测试来自 从计算到临床层面。十个研究组成部分、两个科学核心和一个管理 CORE组成了这个财团。INIA-N将由行政核心指导，并与 执行委员会和指导委员会，并由杰出的科学咨询委员会指导。这个 管理核心将提供领导、科学项目的监督、研究药物的认证以及 项目数据的集成和转换。INIA-N有四个目标：1)扩大我们的啮齿动物和人类基因组 包括非人类灵长类动物的研究(与INIA-Stress合作)和新的啮齿动物模型，以及 将这些与现有数据集集成在一起。我们还将整合遗传学(全基因组关联研究)和 基因组分析(新的人类RNA-Seq数据集)，以促进药物靶标识别，重点是 神经免疫靶标和新的非编码RNA和剪接变异体在酒精中的未知作用 消费；2)将广泛的基因组资源与新的计算方法相结合，以识别 可能会被重新用于治疗AUDS的候选药物。这些药物将在几种动物饮用中进行测试 模型；3)应用系统级方法(电生理学和活脑成像)来了解 过量饮酒会改变大脑功能，重点放在我们最重要的神经免疫目标上；4)选择 从严格的行为和功能测试中脱颖而出的领先候选人在新人类中学习 实验室组件。INIA-N研究包含一种独特的“从基因网络到药物治疗”的方法 应用尖端计算工具从我们广泛的基因组中提名基因靶点和药物 数据库，并在功能和行为分析中系统地测试这些候选者。

PROJECT SUMMARY This is a competing renewal application for the Integrative Neuroscience Initiative on Alcoholism (INIA)- Neuroimmune consortium (Notice# RFA-AA-16-004/005/006) to identify drug targets based on the genomic, cellular, and behavioral neuroadaptations related to excessive alcohol consumption. INIA-Neuroimmune (INIA- N) will address several NIAAA goals, including: 1) understanding the genomics, electrophysiology, and pharmacology of brain immune pathways and their role in alcohol use disorders (AUDs); 2) using new technologies to study neural circuits involved in excessive alcohol drinking; 3) promoting data reproducibility and translation through testing in multiple species (including humans), multiple laboratories, and multiple assays; 4) using emerging computational resources that connect gene networks to drugs to identify compounds with potential to reduce excessive drinking. A key goal for INIA-N is to probe cross-species genomic datasets, together with novel computational approaches, to predict FDA-approved drugs that can be repurposed to treat AUDs. The overall hypothesis for INIA-N is that excessive alcohol consumption causes genetic changes and neuroadaptations in immune-related pathways that are conserved across multiple species (including humans), allowing for the systematic selection and testing of drug targets from the computational to the clinical level. Ten Research Components, two Scientific Cores, and an Administrative Core comprise the consortium. INIA-N will be directed by the Administrative Core in cooperation with the Executive and Steering Committees and guided by a distinguished Scientific Advisory Board. The Administrative Core will provide leadership, oversight of scientific projects, authentication of study drugs, and integration and translation of project data. INIA-N has four goals: 1) Expand our rodent and human genomic studies to include non-human primates (in collaboration with INIA-Stress) and new rodent models, and integrate these with existing datasets. We will also integrate genetic (genome-wide association studies) and genomic analyses (new human RNA-Seq datasets) to facilitate drug target identification, with an emphasis on neuroimmune targets and the unexplored role of novel non-coding RNAs and splice variants in alcohol consumption; 2) Combine extensive genomic resources with new computational approaches to identify candidate drugs that may be repurposed to treat AUDs. These drugs will be tested in several animal drinking models; 3) Apply systems-level approaches (electrophysiology and live brain imaging) to understand how excessive drinking changes brain function, with an emphasis on our top neuroimmune targets; 4) Select leading candidates that emerge from rigorous behavioral and functional testing to study in the new human laboratory component. INIA-N research encompasses a unique `gene network to pharmacotherapy' approach to apply cutting-edge computational tools to nominate gene targets and drugs from our extensive genomic databases and systematically test these candidates in functional and behavioral assays.